Therapeutic guanidines

ABSTRACT

The present invention provides therapeutically useful substituted guanidines, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such guanidines.

This Application is a Continuation of U.S. Ser. No. 08/482,984, filedJun. 7, 1995, which is a Continuation of PCT/US95/01536, filed Feb. 3,1995, which is a Continuation-in-part of U.S. Ser. No. 08/191,793, filedFeb. 3, 1994, now abandoned, the teachings of which are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention pertains to certain substituted guanidines, andmethods of treatment and pharmaceutical compositions that utilize orcomprise one or-more such guanidines.

2. Background

Neurons of the mature central nervous system (“CNS”) are highlyspecialized and in general do not replace themselves. Consequently,death or degeneration of cells in the nervous system can have far moreserious consequences than cell death or degeneration in other organs.Abnormal neuronal death can be rapid and widespread as in traumaticbrain injury, or can occur over many years among very specificpopulations of neurons as in chronic neurodegenerative diseases.

Substantial evidence now points to pernicious overactivity of normalneurotransmitter systems as a contributory mechanism in many instancesof pathological neuronal degeneration. In particular, overstimulation ofneuronal receptors for L-glutamate, the brain's most prevalentexcitatory amino acid (“EAA”) neurotransmitter, has been recognized as acausal or exacerbating factor in several acute neurological disorders,and has been proposed to underlie a number of chronic neurodegenerativediseases as well [Choi, D. W., Neuron., 1:623 (1988); Choi, D. W.,Cerebrov. and Brain Metab. Rev., 2:105 (1990); Albers, G. W., et al.,Ann. Neurol., 25:398 (1989)]. Indeed, it is believed that glutamateneurotoxicity is involved in acute injury to the nervous system asobserved with seizure, hypoxia, hypoglycemia, and trauma, as well as inchronic degenerative diseases such as Huntington's disease,olivopontocerebellar atrophy associated with glutamate dehydrogenasedeficiency and decreased glutamate catabolism, amyotrophic lateralsclerosis/Parkinsonium-dementia, Parkinson's disease, and Alzheimer'sdisease [Choi, D. W., Neuron, 1:623-634 (1988); Choi, D. W., Cereb.Brain Met., Rev. 2:105-147 (1990); Courtier et al., Lancet, 341:265-268(1993); Appel, S. H., Trends Neurosci., 16:3-5 (1993)].

In the mammalian brain, glutamate interacts with three major classes ofreceptors, i.e., N-methyl-D-aspartate (“NMDA”) receptors, non-NMDAreceptors and metabotropic receptors [Watkins, J. D., et al., TrendsNeurosci., 10:265 (1987); and Seeburg, TIPS, 141:297 (1993)]. Whiletriggering distinctive postsynaptic responses, all three classes ofglutamate receptors can act to Increase the intracellular concentrationof free Ca²⁺ in nerve cells [A. B. MacDermott, Nature 321:519 (1986)].Thus, binding of glutamate to the NMDA receptor opens a cation-selectivechannel that is markedly permeable to Ca²⁺, leading to a large and rapidincrease in intracellular Ca²⁺. A subclass of non-NMDA receptors hasbeen found to be linked to a Ca-permeable cation channel [Sommer, B.,and Seeburg, P. H., Trends Pharmacol. Sci. 13:291-296 (1992)]. Althoughnon-NMDA receptors are in most other instances linked to cation channelsthat largely exclude calcium, they can indirectly promote Ca²⁺ entryinto neurons by depolarizing the cell membrane, which in turn opensvoltage-activated Ca²⁺-channels. The so-called “metabotropic receptor”,on the other hand, is not associated with an Ion channel but can promotethe release of Ca²⁺ from intracellular stores via the second-messengerinositol triphosphate.

Irrespective of the triggering mechanism, prolonged elevation ofcytosolic Ca²⁺ is believed to be a key event in the initiation ofneuronal destruction. Adverse consequences of elevated intracellularCa²⁺ include derangement of mitochondrial respiration, activation ofCa²⁺-dependent proteases, lipases and endonucleases, free radicalformation and lipid peroxidation of the cell membrane [Choi, D. W.,Neuron, 1:623-624 (1988)].

The NMDA subtype of excitatory amino acid receptors is strongly involvedin nerve cell death which occurs following brain or spinal chordischemia. Upon the occurrence of ischemic brain insults such as stroke,heart attack or traumatic brain injury, an excessive release ofendogenous glutamate occurs, resulting in the over-stimulation of NMDAreceptors. Associated with the NMDA receptor Is an ion channel. Therecognition site, i.e., the NMDA receptor, is external to the ionchannel. When glutamate interacts with the NMDA receptor, it causes theion channel to open, thereby permitting a flow of cations across thecell membrane, e.g., Ca²⁺ and Na⁺ into the cell and K⁺ out of the cell.It is believed that this flux of ions, especially the influx of Ca²⁺ions, caused by the interaction of glutamate with the NMDA receptor,plays an important role in nerve cell death [see, e.g., Rothman, S. M.and Olney, J. W., Trends in Neurosci., 10(7):299-302 (1987)].Additionally, excessive excitation of neurons occurs in epilepticseizures and it has been shown that over-activation of NMDA receptorscontributes to the pathophyslology of epilepsy [(Porter, R. J.,Epilepsia, 30(Suppl. 1):S29-S34 (1989); and Rogawski, M. A., et al.,Pharmacol. Rev., 42:224-286 (1990)].

Non-NMDA receptors constitute a broad category of postsynaptic receptorsites which, as is the case for NMDA receptors, are directly linked toion channels. Specifically, the receptor sites are physically part ofspecific ion channel proteins. Non-NMDA receptors have been broadlycharacterized into two major subclasses based on compounds selectivetherefor: kainate receptors and AMPA/quisqualate receptors [see J. C.Watkins et al., Trends Neurosci., 10:265 (1987)]. AMPA is anabbreviation for α-amino-3-hydroxyl-5-methyl-4-isoazole propionic acid.These subclasses may be categorized as “non-NMDA” receptors.

Compared to NMDA receptors, non-NMDA receptors have received lesspharmacological scrutiny—the existing antagonists are allcompetitive—and in vivo research In this area has been hampered by thelack of drugs that cross the blood-brain barrier. Nonetheless, in vivostudies have clearly demonstrate that non-NMDA receptor agonists canalso be as excitotoxic, although longer exposures can be required. Inaddition, evidence from animal studies and from human epidemiologicalstudies suggests that excitotoxicity mediated by non-NMDA receptors maybe clinically important in certain pathologies. [see M. D. Ginsberg etal., Stroke, 20:1627 (1989)].

One such disorder is global cerebral ischemia or hypoxia, as occursfollowing cardiac arrest, drowning, and carbon monoxide poisoning.Transient, severe interruption of the cerebral blood supply and/orinterruption of the delivery of oxygen to the brain of animals causes asyndrome of selective neuronal necrosis, in which degeneration occursamong special populations of vulnerable neurons (including neocorticallayers 3, 5 and 6, pyramidal cells in hippocampal zones CA1 and CA3, andsmall and medium sized striatal neurons). The time course of thisdegeneration is also regionally variable, and can range from a few hours(striatum) to several days (hippocampus).

NMDA antagonists generally have not proven highly effective in animalmodels of global ischemia; indeed, it has been suggested that positiveresults obtained using NMDA antagonists may largely be the artifactualresult of induction of hypothermia rather that due to direct inhibitionof NMDA receptor-linked Ca entry into brain neurons [Buchan, A. et al.,J. Neurosci., 11 (1991) 1049-1056]. In contrast, the competitivenon-NMDA receptor antagonist2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (“NBQX”) isdramatically effective in preventing delayed neuronal degenerationfollowing transient forebrain ischemia in both gerbils and rats [M. J.Sheardown et al., Science, 247:571-574 (1990)].

At present, there is a critical need for effective treatments whichlimit the extent of nerve cell death following a stroke or traumaticbrain injury. Recent advances in the understanding of the mechanismsunderlying this nerve cell death have led to the hope that a drugtreatment can be developed. Research and development efforts in thisarea have focussed on blocking the actions of glutamate that aremediated by the NMDA receptor-channel complex. Two approaches have beendeveloped: competitive NMDA receptor antagonists [Choi D. W., Cerebrov.Brain Metab. Rev. 1:165-211 (1990); Watkins, J. C. and Olverman, H. J.,Trends Neurosci., 10:265-272 (1987)] and blockers of the ion channel ofthe NMDA receptor-channel complex [Meldrum, B., Cerebrovascular BrainMetab. Rev. 2:27-57 (1987); Choi, D. W., Cerebrovascular Brain Metab.Rev. 2:105-147 (1987); and Kemp, J. A. et al., Trends Neurosci.,10:265-272 (1987)]. However, some toxicity with certain of theaforementioned agents has been reported has been reported [Olney, J. W.et al., Science. 244:1360-1362 (1989); Koek, W. and Colpaert, J., etal., J. Pharmacol. Exp. Ther., 252:349-357 (1990)].

Blockers of neurotransmitter release, in particular blockers of therelease of glutamate, have also received some attention as potentialneuroprotective agents (see Meldrum, B., Cerebrovascular and BrainMetab., Rev. 2: 27-57 (1990); Dolphin, A. C. Nature, 316:148-150(1985)); Evans, M. C. et al., Neurosci. Lett., 83:287-292 (1987); Ault,B. and Wang, C. M., Br. J. Pharmacol., 87:695-703 (1986); Kaneko, T., etal., Arzneim-Forsch./Drug Res., 39:445-450 (1989); Malgouris, C., etal., J. Neurosci., 9:3720-3727 (1989); Jimonet, P. et al. BioOrgan. andMed. Chem. Lett., 983-988 (1993); Wahl, F. et al., Eur. J. Pharmacol.,230:209-214 (1993); Koek, J. W. and Colpaert, F. C., J. Pharmacol. Exp.Ther., 252:349-357 (1990); Kaneko, T. et al., Arzneim.-Forsch./DrugRes., 39:445-450 (1989)]. Certain compounds said to inhibit glutamaterelease also have been reported to show anticonvulsant activity[Malgouris, C., et al., J. Neurosci., 9: 3720-3727 (1989); Miller, A.A., et al., in New Anticonvulsant Drugs, Meldrum, B. S. and Porter R. J.(eds), London: John Libbey, 165-177 (1986)].

Calcium antagonists acting at L-type Ca channels such as nimodipine havebeen reported to act both as cerebral vasodilators [Wong, M. C. W. etal., Stroke, 24:31-36 (1989)], and to block calcium entry into neurons[Scriabine, A. Adv. Neurosurg., pp. 173-179 (1990)]. Modest improvementin the outcome of stroke has been observed in clinical trials [Gelmers,H. J. et al., N. Eng. J. Med., 318:203-207 (1988)]. While there aresignificant cardiovascular side effects, nimodipine appears less toxicIn other respects than certain NMDA antagonists.

Antagonists of voltage-gated Na channels can exhibit neuroprotectiveproperties. [Graham, S. H., et al., J. Cereb. Blood Flow and Metab.,13:88-97 (1993), Meldrum, B. S., et al., Brain Res., 593:1-6 and Stys,P. K., et al., J. Neurosci., 12: 430-439 (1992)]. In stroke, sustainedhypoxia in the “core region” results from occlusion of the blood supplyby a clot. As hypoxia develops, ATP depletion leads to an inability ofthe Na, K-ATPase to maintain the Ion gradients which generate the normalmembrane potential of resting nerve cells. As the cell depolarizes andreaches the threshold for action potential firing, Na channels areactivated. Stys et al. [Stys, et al., J. Neurosci., 12: 430-439 (1992)]recently reported the development of Na channel hyperactivity in anoxiaof central white matter and demonstrate in vitro the neuroprotectiveeffect of the Na channel blockers tetrodotoxin (TTX) and saxitoxin(STX).

SUMMARY OF THE INVENTION

The present invention provides therapeutically useful substitutedguanidine compounds, including compounds that modulate, particularlyinhibit, the release of a neurotransmitter such as glutamate, andmethods of treatment comprising such compounds. Preferred compounds ofthe invention modulate, particularly inhibit, neurotransmitter (e.g.,glutamate) release from ischemic neuronal cells, especially mammaliancells such as human neuronal cells. The compounds of the invention areuseful for a number of therapeutic applications, including treatment ofthose diseases that result from modulation of a particularneurotransmitter system and that can be counteracted by one or more ofthe substituted guanidines of the invention which act either on the sameor another class of neurotransmitters, and treatment of a variety ofdisorders of the nervous system and cardiovascular system, and ofendocrine function.

In a first aspect, the present invention provides N,N-disubstitutedguanidines of Formula I:

wherein:

R and R¹ are each independently substituted or unsubstituted alkylhaving from 1 to about 20 carbon atoms, substituted or unsubstitutedalkenyl having from 2 to about 20 carbon atoms, substituted orunsubstituted alkynyl having from 2 to about 20 carbon atoms,substituted or unsubstituted alkoxy having from 1 to about 20 carbonatoms, substituted or unsubstituted aminoalkyl having 1 to about 20carbon atoms, substituted or unsubstituted alkylthio having from 1 toabout 20 carbon atoms, substituted or unsubstituted alkylsulfinyl havingfrom 1 to about 20 carbon atoms, substituted or unsubstitutedcarbocyclic aryl having at least about 5 ring atoms, substituted orunsubstituted aralkyl having at least about 5 ring atoms, or asubstituted or unsubstituted heteroaromatic or heteroalicyclic grouphaving from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to3 hetero atoms, with at least one of R and R¹ being carbocyclic aryl,aralkyl, a heteroaromatic group or a heterocyclic group;

R² and R³ each being independently selected from the group consisting ofhydrogen, substituted and unsubstituted alkyl having from 1 to about 20carbon atoms, substituted and unsubstituted alkoxy having from 1 toabout 20 carbon atoms, substituted and unsubstituted alkylthio havingfrom 1 to about 20 carbon atoms, substituted and unsubstitutedalkylsulfinyl having from 1 to about 20 carbon atoms, substituted andunsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, andsubstituted and unsubstituted aminoalkyl; and pharmaceuticallyacceptable salts thereof.

A preferred group of compounds of Formula I are N,N-disubstitutedcompounds of the following Formula IA:

wherein R and R¹ are as defined above for Formula I, andpharmaceutically acceptable salts thereof.

A further preferred group of compounds of Formula I are compounds of thefollowing Formula IB:

wherein R and R¹ are as defined above for Formula I, and R² and R³ eachbeing independently selected from the group consisting of hydrogen,substituted and substituted alkyl having from 1 to about 20 carbonatoms, substituted and unsubstituted alkoxy having from 1 to about 20carbon atoms, substituted and unsubstituted alkylthio having from 1 toabout 20 carbon atoms, substituted and unsubstituted alkylsulfinylhaving from 1 to about 20 carbon atoms, substituted and unsubstitutedalkylsulfonyl having from 1 to about 20 carbon atoms, and substitutedand unsubstituted aminoalkyl, with at least one of R² and R³ being otherthan hydrogen; and pharmaceutically acceptable salts thereof.

Preferred compounds of Formulas I, IA or IB include those compoundswhere at least one, or more preferably both, of R and R¹ is substitutedor unsubstituted carbocyclic aryl or substituted or unsubstitutedaralkyl or substituted or unsubstituted alkaryl. Preferred compounds ofFormulas I, IA and IB include those compounds having substituents with 1to about 6 carbon atoms, particularly R² and/or R³ groups that have 1 to6 carbon atoms. Particularly preferred R² and R³ substituents ofcompounds of Formulas I, IA or IB include unsubstituted alkyl andheteroalkyl such as alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl andaminoalkyl. Preferred R and R¹ groups include substituted andunsubstituted acenaphthyl, phenyl, biphenyl, naphthyl, fluorenyl andbenzyl, particularly alkyl-substituted and alkoxy-substituted phenyl andbenzyl. Particularly preferred R and R¹ groups include straight andbranched chain C₁₋₈-alkyl substituted phenyl and benzyl such astert-butylphenyl, tert-butylbenzyl, sec-butylphenyl, sec-butylbenzyl,n-butylphenyl, n-butylbenzyl, iso-butylphenyl, iso-butylbenzyl,pentylphenyl, pentylbenzyl, hexylphenyl, hexylbenzyl and the like;straight and branched chain C₁₋₈-alkoxy (including haloalkoxy, i.e.alkoxy substituted by F, Cl, Br and/or I) substituted phenyl and benzylsuch as butoxyphenyl, butoxybenzyl, pentoxyphenyl, pentoxybenzyl,hexoxyphenyl, hexoxybenzyl, trifluoromethoxyphenyl, trifluorobenzyl,fluoro and the like; alkaryl (including alkoxyaryl) substituted phenyland benzyl, particularly substituted and unsubstituted benzyl andbenzyloxy (especially —OCH₂C₆H₅). Cycloalkyl and aryl (particularlycarbocyclic aryl) such as substituted phenyl, benzyl and naphthyl arealso preferred R and R¹ groups such as biphenyl, phenylbenzyl (i.e.—CH₂C₆H₄C₆H₅), cyclohexylphenyl, cyclohexylbenzyl and the like. Halo(i.e., F, Cl, Br and/or I) substituted R and R¹ groups are alsopreferred including halo-substituted phenyl, naphthyl and benzyl.

In another aspect, the invention provides compounds of the followingFormula II:

wherein

R is selected from the group of fluorenyl, phenanthracenyl, anthracenyland fluoranthenyl;

R¹ is substituted or unsubstituted alkyl having from 1 to about 20carbon atoms, substituted or unsubstituted alkenyl having from 2 toabout carbon atoms, substituted or unsubstituted alkynyl having from 2to 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 toabout 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1to about 20 carbon atoms, substituted or unsubstituted alkylthio havingfrom 1 to about 20 carbon atoms, substituted or unsubstitutedalkylsulfinyl having from 1 to about 20 carbon atoms, substituted orunsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms,substituted or unsubstituted carbocyclic aryl having at least about 5ring atoms, substituted or unsubstituted aralkyl having at least about 5ring atoms, or a substituted or unsubstituted heteroaromatic orheteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in eachring and 1 to 3 heteroatoms;

R² and R³ are each independently hydrogen or a group as defined for R¹above; and pharmaceutically acceptable salts thereof.

Preferred compounds of Formula II include N,N′-disubstituted compounds,i.e. where R² and R³ are each hydrogen, as well as tri- andtetra-substituted compounds where one or both of R² and R³ are otherthan hydrogen. Preferred R¹ groups include cycloalkyl, particularlyadamantyl, and carbocyclic aryl, particularly substituted orunsubstituted phenyl, naphthyl or acenaphthyl, more preferablysubstituted or unsubstituted phenyl or naphthyl, such as alkyl or alkoxysubstituted phenyl or naphthyl. Alkyl such as methyl, ethyl or propyl isa preferred R² or R³ group.

In a further aspect, the invention provides compounds of the followingFormula III:

wherein R and R¹ are each independently substituted or unsubstitutedalkyl having from 1 to about 20 carbon atoms, substituted orunsubstituted alkenyl having from 2 to about 20 carbon atoms,substituted or unsubstituted alkynyl having from 2 to about 20 carbonatoms, substituted or unsubstituted alkoxy having from 1 to about 20carbon atoms, substituted or unsubstituted aryloxy having from 6 toabout 20 carbon atoms, substituted or unsubstituted aralkoxy having from6 to about 20 carbon atoms, substituted or unsubstituted aminoalkylhaving 1 to about 20 carbon atoms, substituted or unsubstitutedalkylthio having from 1 to about 20 carbon atoms, substituted orunsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms,substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbonatoms, substituted or unsubstituted carbocyclic aryl having at least 5ring atoms, substituted or unsubstituted aralkyl having at least 5 ringatoms, or a substituted or unsubstituted heteroaromatic orheteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in eachring and 1 to 3 heteroatoms;

R² and R³ are each independently hydrogen or a group as defined for Rand R¹ above, and preferably are each substituted or unsubstitutedalkyl, alkenyl, alkynyl, alkoxy, aminoalkyl, alkylthio or alkylsulfinyl;or R¹ and R³ together form a ring having 5 or more ring members;

n and n′ independently are each equal to 1, 2, or 3;

X and X′ are each independently a chemical bond (i.e., a bond betweenthe guanidine nitrogen and R or R¹), substituted or unsubstitutedalkylene having from 1 to about 8 carbon atoms, substituted orunsubstituted alkenylene having from 2 to about 8 carbon atoms, orsubstituted or unsubstituted alkynylene having from 2 to about 8 carbonatoms, substituted or unsubstituted heteroalkylene having from 1 toabout 8 carbon atoms, substituted or unsubstituted hateroalkenylenehaving 2 to about 8 carbon atoms, and substituted or unsubstitutedheteroalkynylene having from 2 to about 8 carbon atoms, with at leastone X and X′ being other than a bond; and pharmaceutically acceptablesalts thereof.

Preferred compounds of Formula III include those where X is substitutedor unsubstituted alkylene or alkenylene having 1 to about 3 carbonatoms, particularly where X is a substituted or unsubstituted alkylenehaving 1 to about 6 carbon atoms, more preferably 1 to about 4 carbonatoms, as specified by the following Formula IIIA:

wherein the groups R, R¹, R² and R³ are as defined above for FormulaIII, and the value n is equal to 1, 2 or 3; and pharmaceuticallyacceptable salts thereof.

Preferred compounds of Formula III include those where R and R¹ togetherform a ring having 5 or more ring atoms, either with the guanidinenitrogen as the sole hetero atom or with one or more other N, O or Satoms as ring members, typically just one other N, O or S ring atom inaddition to the guanidine N. Generally preferred is where R and R¹together form a ring having 5-7 ring atoms, e.g., forming the followingsubstituted or unsubstituted rings: morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, thiomorpholinyl, pyrrolidinyl,piperidinyl and tetrahydroquinolinyl. Preferred substituents of suchrings include e.g. C₁₋₈alkyl, C₁₋₈alkoxy and substituted andunsubstituted alkaryl, particularly substituted and unsubstitutedbenzyl.

Particularly preferred such compounds of Formula III are those of thefollowing Formula IIIB:

wherein R and R² of said formula are each independently substituted orunsubstituted alkyl having from 1 to about 20 carbon atoms, substitutedor unsubstituted alkenyl having from 2 to about 20 carbon atoms,substituted or unsubstituted alkynyl having from 2 to about 20 carbonatoms, substituted or unsubstituted alkoxy having from 1 to about 20carbon atoms, substituted or unsubstituted aryloxy having from 6 toabout 20 carbon atoms, substituted or unsubstituted aralkoxy having from6 to about 20 carbon atoms, substituted or unsubstituted aminoalkylhaving 1 to about 20 carbon atoms, substituted or unsubstitutedalkylthio having from 1 to about 20 carbon atoms, substituted orunsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms,substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbonatoms, substituted or unsubstituted carbocyclic aryl having at least 5ring atoms, substituted or unsubstituted aralkyl having at least 5 ringatoms, or a substituted or unsubstituted heteroaromatic orheteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in eachring and 1 to 3 heteroatoms;

n is 1, 2, or 3, and preferably is 1 or 2, more is preferably 1; W is acarbon atom, or N, O or S; m is an integer of from 0 to 5, andpreferably is 1, 2 or 3, more preferably 0, 1 or 2.

X is substituted or unsubstituted alkylene having from 1 to about 8carbon atoms, substituted or unsubstituted alkenylene having from 2 toabout 8 carbon atoms, or substituted or unsubstituted alkynylene havingfrom 2 to about 8 carbon atoms, substituted or unsubstitutedheteroalkylene having from 1 to about 8 carbon atoms, substituted orunsubstituted heteroalkenylene having 2 to about 8 carbon atoms, andsubstituted or unsubstituted heteroalkynylene having from 2 to about 8carbon atoms, and preferably X is substituted or unsubstituted alkylene,particularly alkylene having 1 to 2 carbon atoms;

each Y substituent is independently halogen, substituted orunsubstituted alkyl having 1 to about 10 carbon atoms, substituted orunsubstituted alkenyl having 2 to about 10 carbon atoms, unsubstitutedalkynyl having 2 to about 10 carbon atoms, substituted or unsubstitutedalkoxy having from 1 to about 10 carbon atoms, substituted orunsubstituted alkylthio having 1 to about 10 carbon atoms, substitutedor unsubstituted aminoalkyl having from 1 to about 10 carbon atoms, orsubstituted or unsubstituted carbocyclic aryl having about 6 or morering members; and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of Formula IIIB are those where R andR₂ are each independently aryl, particularly substituted orunsubstituted carbocyclic aryl such as substituted or unsubstitutedphenyl, substituted or unsubstituted naphthyl or substituted orunsubstituted acenaphthyl.

Especially preferred compounds of Formula IIIB are those where R and R₂are each substituted or substituted phenyl, such as sec-butylphenyl ortert-butylphenyl, particularly para-sec-butylphenyl orpara-tert-butylphenyl, n is 1 and X is alkylene of one or two carbons.Particularly preferred are compounds of the following Formula IIIBB:

wherein W is a carbon atom, or N, O or S;

each Y, each Y′ and each Y″ is each independently halogen, substitutedor unsubstituted alkyl having 1 to about 10 carbon atoms, substituted orunsubstituted alkenyl having 2 to about 10 carbon atoms, unsubstitutedalkynyl having 2 to about 10 carbon atoms, substituted or unsubstitutedalkoxy having from 1 to about 10 carbon atoms, substituted orunsubstituted alkylthio having 1 to about 10 carbon atoms, substitutedor unsubstituted aminoalkyl having from 1 to about 10 carbon atoms, orsubstituted or unsubstituted carbocyclic aryl having about 6 or morering members; n is 1 or 2, and each m, m′ and m″ is independently aninteger of from 0 to 5, and preferably is each m, m′ and m″ isindependently 0, 1, 2 or 3, more preferably 0, 1 or 2; andpharmaceutically acceptable salts thereof. Generally preferred compoundsof Formulas IIIB and IIIBB are those where a Y group is bonded to the Wring member, particularly where W and Y together form a substitutedcarbon atom or N atom such as a C₁₋₈alkyl or C₁₋₈alkoxy substitutedcarbon or nitrogen ring atom. As will be of course understood by thoseskilled in the art, where m, m′ or m″ is 0, the corresponding ring wouldbe “fully” hydrogen-substituted. Specifically preferred compounds ofFormula IIIBB includeN-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)-N′-(4-piperidinyl)guanidine;N-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)-N′-(4-benzylpiperidinyl)guanidine;N-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)-N′-(4-morpholinyl)guanidine;andN-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)-N′-(3,5-dimethyl-4-morpholinyl)guanidine.

A further group of preferred compounds of Formula III are defined thesame as Formulas IIIB and IIIBB above, but where two Y substituents aretaken together to form an aryl or alicyclic fused ring. Generallypreferred is where the fused ring is a heterocyclic or carbocyclic aryl,particularly phenyl, naphthyl, 1,2,3,6-tetrahydroquinolinyl,thiomorpholinyl, pyrolindinyl, piperazinyl and the like, or a cycloalkylsuch as cyclohexyl. A specifically preferred compound isN-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(1,2,3,4-tetrahydroisoquinolinyl)guanidine.

Preferred compounds of Formulas III, IIIA and IIIB include those where Rand/or R¹ is substituted or unsubstituted carbocyclic aryl, particularlysubstituted or unsubstituted phenyl, substituted or unsubstitutednaphthyl or substituted or unsubstituted acenaphthyl. Particularlypreferred are compounds of Formula III and IIIA where R, R¹ and R² areeach substituted or unsubstituted carbocyclic aryl, particularlysubstituted or unsubstituted phenyl, substituted or unsubstitutednaphthyl or substituted or unsubstituted acenaphthyl. Especiallypreferred are compounds of Formula IIIA where R, R¹ and R² are each sucha substituted or unsubstituted carbocyclic aryl, R₃ is hydrogen or C₁₋₄alkyl such as methyl or ethyl, and n is 1 or 2. Of those especiallypreferred compounds one or more of R, R¹ and R² is preferablysubstituted or unsubstituted phenyl e.g. C₁₋₈alkyl-substituted phenylsuch as sec-butylphenyl tert-butylphenyl and the like, halo-substitutedphenyl, C₁₋₈alkoxysubstituted phenyl such as butoxyphenyl orpentoxyphenyl or carbocyclic alkaryloxy-substituted phenyl suchbenzyloxyphenyl.

Preferred compounds of Formula III and IIIA also includeN,N′-disubstituted compounds, i.e. where R² and R³ are each hydrogen, aswell as tri- and tetra-substituted compounds where one or both of R² andR³ are other than hydrogen. Preferred R¹ and R³ groups include alkylsuch as methyl, ethyl or propyl, and substituted alkyl, particularlyhaloalkyl such as C₁-C₈ or C₁-C₄ alkyl substituted by one or more F, Clor Br. Alkylene and heteroalkylene are preferred X or X′ groups,including those heteroalkylene groups containing 1 or 2 N, O, or S atomsas chain members. Particularly preferred X and X′ groups of compounds ofFormulas III, IIIA and IIIB include —CH₂—, —CH₂CH₂—, —CH(CH₃)CH₂— and—CH₂CH(CH₃)—. Preferred compounds of Formulas III and IIIA include thosewhere each R and R¹ group of a compound is bonded to the same carbonatom of the X or X′ chain.

In a further aspect, compounds of the following Formula IV are provided:

wherein

each R is independently halo, hydroxy, amino, nitro, substituted orunsubstituted alkyl having from 3 to about 10 carbon atoms andpreferably from 4 to about 10 carbon atoms, substituted or unsubstitutedalkoxy, substituted or unsubstituted aryloxy, substituted orunsubstituted aralkoxy, substituted or unsubstituted aminoalkyl,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted alkenyl having 3 to about 10 carbon atoms, orsubstituted or unsubstituted alkynyl having 3 to about 10 carbon atoms;

n is an integer of from 1 to 5, preferably from 1 to 3;

R¹ is substituted or unsubstituted alkyl having from 1 to about 20carbon atoms, substituted or unsubstituted alkenyl having from 2 toabout 20 carbon atoms, substituted or unsubstituted alkynyl having from2 to about 20 carbon atoms, substituted or unsubstituted alkoxy havingfrom 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkylhaving 1 to about 20 carbon atoms, substituted or unsubstituted aryloxyhaving from 6 to about 20 carbon atoms, substituted or unsubstitutedalkylthio having from 1 to about 20 carbon atoms, substituted orunsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms,substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbonatoms, substituted or unsubstituted carbocyclic aryl having at least 5ring atoms, substituted or unsubstituted aralkyl having at least 5 ringatoms, or a substituted or unsubstituted heteroaromatic orheteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in eachring and 1 to 3 heteroatoms;

R² and R³ are each independently hydrogen or a group as defined for R¹above; or R² and R³ are taken together to form a substituted orunsubstituted alkylene linkage of from 2 to about 6 carbon atoms; andpharmaceutically acceptable salts thereof.

Preferred compounds of Formula IV include those where one or more Rsubstituents is a branched group such as sec-butyl or tert-butyl, orwhere one or more R substituent is substituted or unsubstitutedaralkoxy, particularly substituted or unsubstituted benzyloxy. The valuen is preferably 1, 2 or 3. Para-substitution and meta-substitution ofthe phenyl group by R substituent(s) is preferred. Preferred compoundsof Formula IV include N,N′-disubstituted compounds, i.e. where R² and R³are each hydrogen, as well as tri- and tetra-substituted compounds whereone or both of R² and R³ are other than hydrogen. Alkyl such as methyl,ethyl or propyl is a preferred R² or R³ group. Substituted orunsubstituted aryl such as substituted or unsubstituted phenyl or benzylare preferred R¹ groups.

A particularly preferred group of compounds of Formula IV are those ofthe following Formula IV(A):

wherein each R′ and R″ are each independepently selected from the samegroup as defined for R of Formula IV above; R² and R³ are defined thesame as in Formula IV above; and n′ and n″ are each an integer of 1 to5, and preferably are each 1 or 2; and pharmaceutically acceptable saltsthereof. It is preferred that n′ and n″ are each 1, and R′ and R″ areeach a meta or para substituent, more preferably each being a parasubstituent. It is further preferred that R′ and R″ are each branchedsubstituents such as tert-butyl, sec-butyl, iso-butyl, iso-pentyl andthe like. Preferably R² and R³ are hydrogen or C₁₋₄alkyl such as methylor ethyl. Specifically preferred compounds of Formula IV(A) includeN,N′-bis(3-sec-butylphenyl)guanidine andN,N′-bis(4-tert-butylphenyl)guanidine. In another aspect, the inventionprovides compounds of said Formula IV(A), particularly for use for themethods of treatment disclosed herein, but where excluded from saidFormula IV(A) are the compounds of N,N′-bis(4-neopentylphenyl)guanidine,N,N′-bis(4-t-butylphenyl)guanidine, N,N′-bis(4-n-butylphenyl)guanidine,and N,N′-bis(4-cyclohexylphenyl)guanidine.

Preferred compounds of Formula IV, particularly for use in methods oftreatment of the invention, also include those compounds wherein R² andR³ are taken together to form a substituted or unsubstituted alkylenelinkage of from 3 to about 6 carbon atoms, particularly compounds withan alkylene linkage of 3 carbon atoms as represented of the followingFormula IV(B):

wherein R, R¹ and n are each the same as defined above for Formula IV,and pharmaceutically acceptable salts thereof. Preferred R¹ groups ofcompounds of Formula IV(B) include substituted and unsubstitutedalkaryl, particularly substituted and unsubstituted benzyl, andsubstituted and unsubstituted carbocyclic aryl, particularly substitutedand unsubstituted phenyl, substituted and unsubstituted naphthyl andsubstituted and unsubstituted acenaphthyl. Preferred substituents ofsuch substituted phenyl, naphthyl or acenaphthyl R¹ groups includeC₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈(mono- or dialkyl)amine, alkoxyaryl andcarbocyclic aryloxy, such as sec-butyl, tert-butyl, hexyl, butyoxy,phenoxy, benzyloxy, and the like.

Specifically, particularly for use in methods of treatment of theinvention, are compounds of the above Formula IV(B) where R¹ is asubstituted or unsubstituted phenyl, as represented by the followingFormula IV(BB):

where each R and R′ are each independently halo, hydroxy, amino, nitro,substituted or unsubstituted alkyl having from 3 to about 10 carbonatoms and preferably from 4 to about 10 carbon atoms, substituted orunsubstituted alkoxy, substituted or unsubstituted aryloxy, substitutedor unsubstituted aralkoxy, substituted or unsubstituted aminoalkyl,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted alkenyl having 3 to about 10 carbon atoms, orsubstituted or unsubstituted alkynyl having 3 to about 10 carbon atoms;and

each n and n′ is independently an integer of from 0 to 5, preferablyfrom 1 to 5, more preferably 1 to 2 or 3. Particularly preferred iswhere each n and n′ is 1. Preferred compounds of Formula IV(BB) includethose where one or more R or R′ substituents is a branched group such asa branched alkyl group e.g. sec-butyl or tert-butyl, or where one ormore R substituent is substituted or unsubstituted aralkoxy,particularly substituted or unsubstituted benzyloxy. Para-substitutionand meta-substitution of the phenyl group by R and R′ substituent(s) istypically preferred. Particularly preferred is where n and n′ are each1, and R and R′ are each para substituents. Preferred R and R′substituents include alkoxy and alkoxyaryl, such as butoxy, pentoxy,hexoxy, substituted and unsubstituted benzyloxy and the like.Specifically preferred compounds of Formula IV(BB) includeN,N′-bis-(alkylphenyl)-2-iminopyrimidazolidine includingN,N′-bis-(butylphenyl)-2-iminopyrimidazolidine,N,N′-bis-(pentylphenyl)-2-iminopyrimidazolidine, andN,N′-bis-(hexylphenyl)-2-iminopyrimidazolidine.

The invention also includes compounds of Formulas IV(B) or IV(BB) wheretwo R substituents or two R′ substituents together form a ring fused tothe phenyl ring. Preferred fused rings have 5 to about 7 or 8 ringmembers and may be a carbocyclic aryl or saturated carbon ring, or aheteroaromatic or heteroalicyclic ring having 1 or 2 N, O or S atoms.Exemplary fused rings include e.g. tetralinyl, indane, or a saturatedsix carbon ring to form a tetralinyl fused ring.

In another aspect, acenaphthyl-substituted guanidines of the followingFormula V are provided:

wherein:

R is substituted or unsubstituted heteroaromatic containing 1-3 rings, 3to 8 ring members in each ring and 1-3 heteroatoms;

R¹ and R² are each independently hydrogen, substituted or unsubstitutedalkyl having from 1 to about 20 carbon atoms, substituted orunsubstituted alkenyl having from 2 to about 20 carbon atoms,substituted or unsubstituted alkynyl having from 2 to about 20 carbonatoms, substituted or unsubstituted alkoxy having from 1 to about 20carbon atoms, substituted or unsubstituted aminoalkyl having from 1 toabout 20 carbon atoms, substituted or unsubstituted alkylthio havingfrom 1 to about 20 carbon atoms, substituted or unsubstitutedalkylsulfinyl having from 1 to about 20 carbon atoms, substituted orunsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms,substituted or unsubstituted carbocyclic aryl having at least 5 ringatoms, substituted or unsubstituted aralkyl having at least 5 ringatoms, or a substituted or unsubstituted heteroaromatic orheteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in eachring and 1 to 3 heteroatoms;

and pharmaceutically acceptable salts thereof.

Preferred R groups of Formula V include 1,2,3,4-tetrahydroquinolinyl,indolinyl, piperonyl, benz[cd]indolinyl and [benz[cd]indo-2[1H]-one. Theabove depicted acenaphthyl group preferably is substituted by theguanidine nitrogen at the 3-position or 5-position. Preferred compoundsof Formula V include N,N′-disubstituted compounds, i.e. where R¹ and R²are each hydrogen, as well as tri- and tetra-substituted compounds whereone or both of R¹ and R² are other than hydrogen. Alkyl such as methyl,ethyl or propyl is a preferred R¹ and R² group of compounds of FormulaV.

At least some compounds of the invention may exist as any one of anumber of tautomeric forms. Each of these tautomeric forms are withinthe scope of the invention, including as defined by the formulasspecified herein.

The present invention includes methods for treatment and/or prophylaxisof neurological conditions such as epilepsy, neurodegenerativeconditions and/or nerve cell death resulting from, e.g., hypoxia,hypoglycemia, brain or spinal chord ischemia, brain or spinal chordtrauma, stroke, heart attack, drowning or carbon monoxide poisoning. Inthis regard, compound of the invention are particularly useful toadminister to mammals, particularly humans, susceptible or sufferingfrom stroke or heart attack. Compounds of the invention also are usefulto treat and/or prevent various neurodegenerative diseases such asParkinson's disease, Huntington's disease, Amyotrophic LateralSclerosis, Alzheimer's disease, Down's Syndrome. Korsakoff's disease,olivopontocerebellar atrophy, HIV-induced dementia and blindness ormulti-infarct dementia. Compounds of the invention also may be used totreat anxiety, e.g. by administration to subjects susceptible togeneralized anxiety disorder. Compounds of the invention will haveparticular utility for treatment of global cerebral ischemia as mayoccur following cardiac arrest, drowning and carbon monoxide poisoning.Compounds of the invention also may be used to treat other disorders ofthe nervous system, disorders of the cardiovascular system such ashypertension, cardiac arrhythmias or angina pectoris, endocrinedisorders such as acromegaly and diabetes insipidus, as well as use fortreatment of chronic pain and as a local anesthetic. Compounds of theinvention will have further utility for the treatment of those diseasesin which the pathophysiology of the disorder involves excessiveotherwise inappropriate (e.g., hypersecretory) cellular secretion, e.g.,secretion of an endogenous substance such as a catecholamine, a hormoneor a growth factor. Exemplary diseases are specifically discussed infra.Compounds of the invention also will have utility for the treatment ofthose diseases in which the pathophysiology of the disorder involvesexcessive or otherwise inappropriate (e.g., hypersecretory) cellularsecretion, e.g., secretion of an endogenous substance such as acatecholamine, a hormone or a growth factor. The methods of treatment ofthe invention (which includes prophylactic therapy) generally compriseadministration of a therapeutically effective amount of one or morecompounds of the invention to an animal, including a mammal,particularly a human.

Further provided are diagnostic methods comprising use of the compoundsof the invention. More specifically, a compound of the invention can besuitably labelled such as by radiolabelling a compound with ¹²⁵I,tritium, ³²P, ⁹⁹Tc, or the like, preferably ¹²⁵I. The labelled compoundcan be administered to a subject such as a human and the subject imagedfor a disease or disorder involving ion-channel activity such as stroke.

The invention also provides pharmaceutical compositions that compriseone or more compounds of the invention and a suitable carrier.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that compounds of the invention have the ability tomodulate, i.e. inhibit or potentiate the release of neurotransmitter(s),or to decrease or lengthen the time course of release ofneurotransmitter(s), from neuronal tissue. It has thus been found thatthe compounds will have utility to treat or prevent thosepathophysiologic conditions which result from excessive or inadequaterelease of neurotransmitters. It is thought that substituted guanidinesof the invention mediate the inhibition of neurotransmitter release byblocking presynaptic calcium channels and/or sodium channels.Accordingly, the invention provides methods for blockage ofvoltage-activated calcium channels or sodium channels of neuronal cells,particularly mammalian cells such as human neuronal cells, comprisingthe administration to the cells of an effective amount of a compound ofthe invention, particularly such administration to a mammal in need ofsuch treatment. By such blockage of calcium channels and/or sodiumchannels of neuronal cells, conditions associated with excessiveendogenous neurotransmitter release can be treated.

More particularly, some disorders such as neuronal damage in stroke maybe alleviated by inhibiting the release of excitatory amino acids suchas glutamate. Some disorders such as depression may be alleviated byinhibiting the release of inhibitory neurotransmitters such asgamma-aminobutyric acid. Further and without wishing to be bound bytheory, inhibiting the release of an excitatory neurotransmitter such asglutamate by administration of a compound of the invention mayindirectly potentiate the release or subsequent actions of an inhibitorytransmitter such as gamma-aminobutyric acid, and thus the compound ofthe invention may treat disorders known to be alleviated by more directpotentiation of inhibitory neurotransmission, e.g., anxiety or insomnia.

Compounds of the invention may be considered effective inhibitors ofneurotransmitter release if the compound causes at least about a 50%inhibition of neurotransmitter release, such as release of glutamate, ata concentration of about 100 μM according to the protocol disclosed inExample 146 infra. More preferably the compound will cause at leastabout a 50% inhibition of release of a neurotransmitter, such asglutamate, at a concentration of about 30 μm according to the protocoldisclosed in Example 146 infra. As used herein, the phrase “highinhibition of glutamate release” indicates that the specifiedcompound(s) will cause at least 50% inhibition of glutamate release at aconcentration of about 100 μM according to the protocol disclosed inExample 146 infra.

Compounds of the invention may modulate release of neurotransmittersthat include glutamate, dopamine, GABA (δ-amino butyric acid),norepinephrine, glycine, aspartate, serotonin, acetylcholine, adenosinetriphosphate and epinephrine, particularly glutamate. Compounds of theinvention also may modulate release of peptides such as tachykinins,including substance P and substance k, enkephalins, luteinizinghormone-releasing hormone (LHRH) or derivatives thereof (seeHarrington's Principles of Internal Medicine, 1705 (McGraw Hill 1987)),bombesin, chotecystokinin, neuropeptide Y, dynorphin, gastrin-releasinghormone (GRH), neurotensin, somatostatin, and vasoactive intestinalpeptide (VIP).

Specifically, compounds of the invention show significant ability toblock depolarization-stimulated, calcium-dependent glutamate releasefrom brian synaptosomes, when tested by the rapid superfusion methoddescribed in Example 146, infra. Said method identifies compounds thatact to block voltage-activated presynaptic Ca channels in nerveterminals, but may also identify compounds that block glutamate releaseby interfering with other processes involved in the control ofCa-dependent glutamate release. Compounds of the invention havedemonstrated significant (≧50%) attenuation of glutamate release atconcentrations of 10 μM or less, and many are effective atconcentrations at or below 3 μM. See, e.g., Table I of Example 146,infra. Moreover, these compounds of the invention exhibit relatively lowbinding affinity for the ion channel of the NMDA subclass of glutamatereceptors and the di-tolyl guanidine (DTG) binding site associated withthe sigma receptor. This indicates that compounds of the invention havea clearly distinct therapeutic mechanism of action relative to that ofknown compounds which exhibit high affinity for either the ion channelof the NMDA subclass of glutamate receptors, and/or the DTG binding siteof sigma receptors.

More particularly, a number of preferred compounds of the invention,including compounds of Formula IV and IV(A), will exhibit highinhibition of glutamate release (as that phrase is defined to meanabove), but relatively low affinity for the PCP receptor, specificallyan IC₅₀ of 5 to 100 μM or more in a typical PCP receptor assay asdescribed in U.S. Pat. No. 4,906,779 (see columns 10-11). A number ofpreferred compounds of the invention also will exhibit high inhibitionof glutamate release, but relatively low affinity for the sigma receptorin a typical sigma receptor binding assay such as the assay disclosed inWeber et al., Proc. Natl. Acad. Sci. (USA), 83:8784-8788 (1986),specifically an IC₅₀ of 10-200 μM or more in the DTG sigma binding assaydisclosed in Weber et al., Proc. Natl. Acad. Sci. (USA), 83:8784-8788(1986). As used herein, the phrase “low affinity to the NMDA receptor”is intended to mean the specified compound(s) exhibits an IC₅₀ of 5 to100 μM or greater in said PCP receptor assay described in U.S. Pat. No.4,906,779; and the term “low affinity to the sigma receptor” is intendedto mean the specified compound(s) exhibits an IC₅₀ of 10-200 μM orgreater in the DTG sigma binding assay disclosed in Weber et al., Proc.Natl. Acad. Sci. (USA), 83:8784-8788 (1986).

The preferred mechanism which underlies the ability of compounds of theinvention to block neurotransmitter release in vivo is blockade ofvoltage-activated Na channels and/or Ca channels which regulateneurotransmitter release [McBurney et al., J. Neurotrauma, 9, Suppl.2:S531-S543 (1992); Kattragadda, S. et al., Abs. Soc. for NeuroSci.Abs., 18:436 (1992)]. Examples 146-148 below describe the ability ofcompounds of the invention to block said voltage-activated Na and Cachannels, providing further indication that compounds of the inventionwill effectively block release of a variety of neurotransmitters uponadministration of the compounds to a mammal including a human.

Secretion of a variety of substances from non-neuronal secretory cellsoccurs by a process of Ca-dependent exocytosis closely resembling themechanism of Ca-dependent neurotransmitter release [Rubin, R. P.,Pharmacol. Rev., 22:389-428 (1970)]. Examples of this include release ofnorepinephrine from adrenal chromaffin cells [Landsberg, L. et al.,Harrington's Principles of Internal Medicine, 11th Ed., eds., New York,McGraw-Hill, pp.358-370 (1987); Neher, E. et al., Neuron, 10:21-30(1993)], secretion of peptide hormones from the pituitary [Tse et al.,Science, 260:82-84 (1993); Chang, J. P. et al., Endocrinology, 123:87-94(1988)], secretion of digestive enzymes from pancreatic acinar cells[Muallem, S., Ann. Rev. Physiol., 51:83-105 (1989)], and secretion ofinsulin from pancreatic beta cells [Larner, J., The PharmacologicalBasis of Therapeutics, 7th Ed., eds., New York, MacMillan, pp. 1490-1503(1985)]. The voltage-activated Ca channels that play a major role ingoverning said processes resemble those that govern neurotransmitterrelease, in terms of structure, pharmacology, and mechanism [Bean, B.P., Ann. Rev. Physiol. 51:367-384 (1989); Hess, P., Ann. Rev. Neurosci.13:337-56 (1989); Cohen, C. J. et al., J. Physiol., 387:195-225 (1987)].Accordingly the ability of compounds of the invention to blockneurotransmitter release as described in Example 146, infra and theability of said compounds to block the activity of voltage-activated Cachannels described in Examples 147 and 148, infra, constitutes strongevidence that compounds of the invention will be effective inhibitors ofexocytotic secretion of a variety of substances from a variety ofnon-neuronal cells. In particular, Example 148 demonstrates the abilityof compounds of the invention to block Ca channels in GH4C1 clonalpituitary cells. Said pituitary cells secrete prolactin and growthhormone (Tashjian, A. H. Meth. Enyzmol., 58:527-535, Acad. Press, N.Y.(1979)]. Block of voltage-activated Ca channels of pituitary GH4C1 cellsinhibits secretion of said peptides [Tan, K. N. et al., J. Biol. Chem.,259:418-426 (1984)]. Therefore, the results disclosed in Example 148indicate compounds of the invention can function as effectiveantisecretory agents.

Example 147 infra, describes the ability of a subset of the compounds ofthe invention to block the presynaptic voltage-activated Ca channelswhich regulate release of neurotransmitters from mammalian brainsynaptosomes. Said presynaptic Ca channels are structurally andfunctionally related, and in some instances are identical, to Cachannels found in the cell bodies of neurons in the brain, elsewhere inthe central nervous system, and in the peripheral nervous system [Zhang,J. F. et al., Neuropharmacol., 32:1075-1088 (1993); Snutch, T. P. etal., Curr. Opin. Neurobiol., 2:247-253 (1992)]. Therefore, the resultsdisclosed in Example 147 indicate the general ability of compounds ofthe invention to block neuronal Ca channels.

Example 149 infra, describes the ability of a subset of the compounds ofthe invention to block Type II (alias R_(II)) voltage-activated Nachannels, which are identical or closely related to the presynaptic andaxonal voltage-activated Na channels which also govern release ofneurotransmitters from mammalian brain synaptosomes [Westenbrook et al.Neuron, 3:695-704 (1989); Catterall, W. A., Physiolog. Rev., 72:S15-S48(1992]. Said presynaptic and axonal Type II Na channels are structurallyand functionally similar, and in some instances are identical, to Nachannels found in the cell bodies of neurons in the brain; elsewhere inthe central nervous system; the peripheral nervous system; the cardiacconduction system comprising the Purkinje cell network and the atrialbundle branches; and cardiac, skeletal, and smooth muscle cells[Catterall, W. A., ibid.; Trimmer, J. S. et al., Ann. Rev. Physiol.,51:401-418 (1989)].

Example 148 infra describes the ability of a subset of the compounds ofthe Invention to block L-type voltage-activated Ca channels. L-type Cachannels regulate release of certain peptide neurotransmitters frommammalian brain nerve terminals [Rane et al., Pflugers Arch.,409:361-366], and the secretion of a variety of substances such aspeptide hormones of the pituitary [DeRiemer, S. A. et al., Exp. BrainRes. Suppl. 14:139-154 (1986)]. Said L-type Ca channels are structurallyand functionally related, and in some instances are identical, to L-typeCa channels found in the cell bodies of neurons in the brain; elsewherein the central nervous system; the peripheral nervous system; thecardiac conduction system comprising the Purkinje cell network and theatrial bundle branches; and cardiac, skeletal, and smooth muscle cells[Bean, B. P., Ann. Rev. Physiol., 51:367-384 (1989); Snutch, T. P. etal., Curr. Opin. Neurobiol. 2:247-253 (1992)]. Therefore, the resultsdisclosed in Example 148 indicate the ability of compounds of theinvention to block said channels in the aforementioned tissues.

Compounds of the invention may be considered effective blockers of saidvoltage-activated Na and Ca channels if the compound causes at least a50% reduction of the flow of cations through said channels atconcentrations of about 100 μM according to the protocols disclosed inExamples 146-148, infra. More preferably the compound will cause atleast a 50% inhibition of cation flow through said channels at aconcentration of about 10 μM according to the protocols of said Examples146-148, infra.

Compounds of the invention have also demonstrated anticonvulsantactivity in an in vivo as disclosed in Example 150, infra.

Suitable halogen groups of compounds of the invention (includingcompounds of Formulas I, IA, IB, II, III, IIIA, IIIB, IIIBB, IV, IV(A),IV(B), IV(BB) or V as specified above) are F, Cl, Br and I. Preferredalkyl groups include those having 1 to about 12 carbon atoms, morepreferably 1 to about 10 carbon atoms such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, pentyl, hexyl,heptyl, etc. Preferred alkenyl and alkynyl groups include those groupshaving one or more unsaturated linkages, preferably one or twounsaturated linkages and from 2 to about 12 carbon atoms, morepreferably 2 to about 8 carbon atoms. Each of the terms alkyl, alkenyland alkynyl as used herein refer to both cyclic and noncyclic groups,although typically straight or branched chain noncyclic groups aregenerally more preferred. Preferred alkoxy groups of compounds of theinvention include groups having one or more oxygen linkages and from 1to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms,still more preferably 1 to about 6 carbons. Straight and branched chainbutocy, pentoxy, and hexoxy are particularly preferred. Preferredaryloxy groups have 6 to about 20 carbon atoms or from 6 to about 12carbon atoms and include an oxygen atom. Substituted or unsubstitutedphenoxy and naphthoxy are preferred aryloxy groups. Preferred aralkoxygroups have from 6 to about 20 carbon atoms and include an alkoxy groupas specified above that contains one or more aryl substituents,particularly one or more carbocyclic aryl substituents. Typically anoxygen will be the terminal group of the substituent. Substituted orunsubstituted benzyloxy (i.e., C₆H₅CH₂O—) are preferred aralkoxy groups.Preferred thioalkyl groups include groups having one or more thioetherlinkages and from 1 to about 12 carbon atoms, more preferably 1 to about8 carbon atoms, still more preferably 1 to about 6 carbons. Preferredaminoalkyl groups include those groups having one or more primary,secondary and/or tertiary amine groups, and from 1 to about 12 carbonatoms, more preferably 1 to about 8 carbon atoms, still more preferably1 to about 6 carbons. Secondary and tertiary amine groups are generallymore preferred than primary amine moieties. Preferred alkylsulfinylgroups have one or more sulfinyl (SO) groups, more typically onesulfinyl group, and from 1 to about 12 carbon atoms, more preferably 1to about 6 carbons, and even more preferably 1-3 carbon atoms. Preferredalkylsulfonyl groups have one or more sulfono (SO₂) groups, moretypically one sulfono group, and from 1 to about 12 carbon atoms, morepreferably 1 to about 6 carbons, and even more preferably 1-3 carbonatoms. Preferred alkenylene and alkynylene X and X′ groups of compoundsof Formulas III and IIIA have one or two carbon-carbon multiple bonds.Preferred heteroalkylene, heteralkenylene and heteroalkynylene X and X′groups of compounds of Formulas III and IIIA contain 1 to about 3 heteroatoms consisting of N, O and/or S atoms, where one or more of saidhetero atoms is a chain member of the X or X′ group, and more preferablycontain about 1-3 carbon atoms in addition to said hetero atoms.Suitable heteroaromatic and heteroalicyclic groups of compounds of theinvention contain one or more N, O or S atoms and include, e.g.,quinolinyl including 8-quinolinyl, indolinyl including 5-indolinyl,furyl, thienyl, pyrrolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl,oxazolyl and phthalimido groups all of which may be optionallyindependently substituted at one or more available positions and/orfused to a benzene ring; and substituted or unsubstitutedtetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl,morpholino, pyrrolidinyl groups, pyrazinyl, coumarinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiazolyl,benzotriazolyl, and bezimidazolyl. Preferred carbocyclic aryl groupsinclude those having about 6 to about 20 carbons, more preferably about1 to 3 separate or fused rings and from 6 to about 18 carbon atoms suchas phenyl, naphthyl, acenaphthyl, phenanthryl, anthracyl and fluorenegroups.

Said substituted moieties of compounds of the invention may besubstituted at one or more available positions by one or more suitablegroups such as, e.g., halogen such as F, Cl, Br, or I; cyano; hydroxyl;nitro; azido; carboxy; carbocyclic aryl; alkyl groups including alkylgroups having from 1 to about 12 carbon atoms or from 1 to about 6carbon atoms; alkenyl and alkynyl groups including groups having one ormore unsaturated linkages and from 2 to about 12 carbon atoms or from 2to about 6 carbon atoms; alkoxy groups such as those groups having oneor more oxygen linkages and from 1 to about 12 carbon atoms or from 1 toabout 6 carbon atoms; thioalkyl groups such as those groups having oneor more thioether linkages and from 1 to about 12 carbon atoms or from 1to about 6 carbon atoms; aminoalkyl groups such as groups having one ormore N atoms and from 1 to about 12 or 1 to about 6 carbon atoms;alkylsulfinyl such as those groups having one or more sulfinyl groupsand from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms;alkylsulfonyl such as those groups having one or more sulfono groups andfrom 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms.

Specifically preferred substituted groups include carboxylic acylgroups, preferably having from 1 to about 12 or 1 to about 6 carbonatoms such as acetyl, propanoyl, iso-propanoyl, butanoyl, sec-butanoyl,pentanoyl and hexanoyl groups. Also preferred substituted moieties arealkaryl groups which include single and multiple ring compounds,including multiple ring compounds that contain separate and/or fusedaryl groups, e.g., above-mentioned aryl groups substituted by one ormore C₃-C₁₀ alkyl groups such as phenylpropyl, phenylbutyl, phenylpentyland phenylhexyl groups as well as the branched chain isomers thereofsuch as tert-butylphenyl, sec-butylphenyl, etc. Haloalkyl and haloalkoxyare also preferred, particularly fluoroalkyl and fluoroalkoxy such astrifluoromethyl and trifluoroalkoxy. Aroyl groups are also preferredsubstituted groups such as carbonyl substituted by phenyl, naphthyl,acenaphthyl, phenanthryl, and anthracyl groups and carboxylic acylgroups substituted by one or more aryl groups, e.g., diphenylacetoxy andfluorenecarboxy groups. Aralkanoyl groups are also preferred and includecarbonyl substituted by the aralkyl groups described above. Aralkoxygroups are also preferred substituted groups and Include alkoxy groupssubstituted by phenyl, naphthyl, acenaphthyl, phenanthyl, and anthracylgroups. Preferred substituted aryl groups include the above describedaryl groups substituted by halo, hydroxy, alkyl, alkenyl, alkynyl,alkoxy, amino, aminoalkyl, thioalkyl and the like.

Particularly preferred R and R¹ substituent groups of compounds ofFormula I, as defined above, include substituted and unsubstitutedcarbocyclic aryl such as phenyl, butylphenyl including tert-butylphenyl,cyclohexylphenyl, butoxyphenyl, trifluoromethoxyphenyl, halophenyl,methylthiophenyl, acenaphthyl, naphthyl including substituted naphthylsuch as methoxy-1-naphthyl, and the like; and aralkyl groups includingsubstituted and unsubstituted benzyl groups such as tert-butylbenzyl,isopropylbenzyl, halobenzyl, trifluoromethoxybenzyl, cinnamylmethylene,naphthylmethylene, benzyloxy and the like.

Specifically preferred compounds of Formula I include:

N-(4-sec-butylphenyl)-N-benzylguanidine;

N-(5-acenaphthyl)-N-benzylguanidine;

N-(3-acenaphthyl)-N-benzylguanidine;

N-(5-acenaphthyl)-N-(4-isopropylbenzyl)guanidine;

N-(3-acenaphthyl)-N-(4-isopropylbenzyl)guanidine;

N-(4-cyclohexylphenyl)-N-(4-isopropylbenzyl)guanidine;

N-(4-cyclohexylphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(2-fluorenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(4-sec-butylphenyl)-N-(cinnamylmethylene)guanidine;

N-(4-n-butoxyphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(3-biphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(5-indanyl)-N-(4-tert-butylbenzyl)guanidine;

N-(3-trifluoromethoxyphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(5-acenaphthyl)-N-(4-tert-butylbenzyl)guanidine;

N-(3-acenaphthyl)-N-(4-tert-butylbenzyl)guanidine;

N-(methoxy-1-naphthyl)-N-(4-tert-butylbenzyl)guanidine;

N-(1-naphthyl)-N-(4-tert-butylbenzyl)guanidine;

N-(3-iodophenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(4-chloro-1-naphthyl)-N-(4-tert-benzyl)guanidine;

N-(4-tert-butylphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(4-iodophenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(1-naphthylmethyl)-N-(4-tert-butylbenzyl)guanidine;

N-(5-acenaphthyl)-N-(3-phenoxybenzyl)guanidine;

N-(3-trifluoromethylphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(3-methylthiophenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(5-acenaphthyl)-N-(3-iodobenzyl)guanidine;

N-(5-acenaphthyl)-N-(cinnamyl)guanidine;

N-(5-acenaphthyl)-N-(4-iodobenzyl)guanidine;

N-(5-acenaphthyl)-N-(4-trifluoromethoxybenzyl)guanidine;

and pharmaceutically acceptable salts thereof.

Specifically preferred compounds of Formula II include:

N,N′-bis(2-fluorenyl)guanidine;

N,N′-bis(2-fluorenyl)-N-methylguanidine;

N,N′-bis(2-fluorenyl)-N,N′-dimethylguanidine;

N,N′-bis(anthracenyl)guanidine;

N,N′-bis(anthracenyl)-N-methylguanidine;

N,N′-bis(anthracenyl)-N,N′-dimethylguanidine;

N,N′-bis(phenanthracenyl)guanidine;

N,N′-bis(phenanthracenyl)-N-methylguanidine;

N,N′-bis(phenanthracenyl)-N,N′-dimethylguanidine;

N,N′-bis(fluoranthenyl)guanidine;

N,N′-bis(fluoroanthenyl)-N-methylguanidine;

N,N′-bis(fluoroanthenyl)-N,N′-dimethylguanidine;

N-(anthracenyl)-N′-(1-adamantyl)guanidine;

N-(anthracenyl)-N′-(1-adamantyl)-N-methylguanidine;

N-(anthracenyl)-N′-(1-adamantyl)-N′-methylguanidine;

N-(anthracenyl)-N′-(1-adamantyl)-N,N′-dimethylguanidine;

N-(anthracenyl)-N′-(2-adamantyl)guanidine;

N-(anthracenyl)-N′-(2-adamantyl)-N-methylguanidine;

N-(anthracenyl)-N′-(2-adamantyl)-N′-methylguanidine;

N-(anthracenyl)-N′-(2-adamantyl)-N,N′-dimethylguanidine;

N-(phenanthracenyl)-N′-(1-adamantyl)guanidine;

N-(phenanthracenyl)-N′-(1-adamantyl)-N-methylguanidine;

N-(phenanthracenyl)-N′-(1-adamantyl)-N′-methylguanidine;

N-(phenanthracenyl)-N′-(1-adamantyl)-N,N′-dimethylguanidine;

N-(phenanthracenyl)-N′-(2-adamantyl)guanidine;

N-(phenanthracenyl)-N′-(2-adamantyl)-N-methylguanidine;

N-(phenanthracenyl)-N′-(2-adamantyl)-N′-methylguanidine;

N-(phenanthracenyl)-N′-(2-adamantyl)-N,N′-dimethylguanidine;

N-(fluorenyl)-N′-(1-adamantyl)guanidine;

N-(fluorenyl)-N′-(1-adamantyl)-N-methylguanidine;

N-(fluorenyl)-N′-(1-adamantyl)-N′-methylguanidin;

N-(fluorenyl)-N′-(1-adamantyl)-N,N′-dimethylguanidine;

N-(fluorenyl)-N′-(2-adamantyl)guanidine;

N-(fluorenyl)-N′-(2-adamantyl)-N-methylguanidine;

N-(fluorenyl)-N′-(2-adamantyl)-N′-methylguanidine;

N-(fluorenyl)-N′-(2-adamantyl)-N,N′-dimethylguanidine;

N-(fluorenyl)-N′-(methoxynaphthyl)guanidine;

N-(fluorenyl)-N′-(methoxynaphthyl)-N-methylguanidine;

N-(fluorenyl)-N′-(methoxynaphthyl)-N′-methylguanidine;

N-(fluorenyl)-N′-(methoxynaphthyl)-N,N′-dimethylguanidine:

and pharmaceutically acceptable salts of said compounds.

Particularly preferred R substituent groups of compounds of Formulas IIIand IIIA, as those formulas are defined above, include phenyl andnaphthyl. Preferred values of n, n′ and m of compounds of Formulas IIIand IIIA are 1 and 2. The R groups are suitably the same where n isgreater than one. Carbocyclic aryl groups of compounds of Formulas IIIand IIIA are preferred R¹ groups, particularly substituted andunsubstituted phenyl, naphthyl and acenaphthyl. Preferred X groups ofcompounds of Formulas III and IIIA include alkenylene groups substitutedby halogen of F, Cl, Br and I; aryloxy such as substituted andunsubstituted phenoxy; aryl such as substituted and unsubstituted phenylincluding phenyl substituted by C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen suchas F, Cl, Br or I.

Specifically preferred compounds of Formulas III and IIIA include:

N-5-acenaphthyl-N′-benzhydrylguanidine;

N-5-acenaphthyl-N′-benzhydryl-N-methylguanidine;

N-5-acenaphthyl-N′-benzhydryl-N′-methylguanidine;

N-5-acenaphthyl-N′-benzhydryl-N,N′-dimethylguanidine;

N-3-acenaphthyl-N′-benzhydrylguanidine;

N-3-acenaphthyl-N′-benzhydryl-N-methylguanidine;

N-3-acenaphthyl-N′-benzhydryl-N′-methylguanidine;

N-3-acenaphthyl-N′-benzhydryl-N,N′-dimethylguanidine;

N-(5-acenaphthyl)-N′-[(1-naphthyl)-methyl]guanidine;

N-(5-acenaphthyl)-N′-[(1-naphthyl)-methyl]-N-methylguanidine;

N-(5-acenaphthyl)-N′-[(1-naphthyl)-methyl]-N′-methylguanidine;

N-(5-acenaphthyl)-N′-[(1-naphthyl)-methyl]-N,N′-dimethylguanidine;

N-(5-acenaphthyl)-N′-(1-methyl-2-phenoxyethyl)guanidine;

N-(5-acenaphthyl)-N′-(1-methyl-2-phenoxyethyl)-N-methylguanidine;

N-(5-acenaphthyl)-N′-(1-methyl-2-phenoxyethyl)-N′-methylguanidine;

N-(5-acenaphthyl)-N′-(1-methyl-2-phenoxyethyl)-N,N′-dimethylguanidine;

N-(5-acenaphthyl)-N′-(1-methyl-2-(4-chlorophenyl)ethyl)guanidine;

N-(5-acenaphthyl)-N′-(1-methyl-2-(4-chlorophenyl)ethyl)-N-methylguanidine;

N-(5-acenaphthyl)-N′-(1-methyl-2-(4-chlorophenyl)ethyl)-N′-methylguanidine;

N-(5-acenaphthyl)-N′-(1-methyl-2-(4-chlorophenyl)ethyl)-N,N′-dimethylguanidine;

N-(5-acenaphthyl)-N′-(1,2-diphenylethyl)guanidine:

N-(5-acenaphthyl)-N′-(1,2-diphenylethyl)-N-methylguanidine;

N-(5-acenaphthyl)-N′-(1,2-diphenylethyl)-N′-methylguanidine;

N-(5-acenaphthyl)-N′-(1,2-diphenylethyl)-N,N′-dimethylguanidine;

N-(5-acenaphthyl)-N′-(3-phenylpropyl)guanidine;

N-(5-acenaphthyl)-N′-(3-phenylpropyl)-N-methylguanidine;

N-(5-acenaphthyl)-N′-(2-methyl-2-phenylethyl)-N′-methylguanidine;

N,N′-(sec-butylphenyl)-N′-(2-phenoxyethyl)guanidine;

N,N′-(sec-butylphenyl)-N′-(2-phenoxyethyl)-N-methylguanidine;

N,N′-(sec-butylphenyl)-N′-(2-phenoxyethyl)-N′-methylguanidine;

N,N′-(sec-butylphenyl)-N′-(2-phenoxyethyl)-N,N′-dimethylguanidine;

N-(5-acenaphthyl)-N′-((4-tert-butylphenyl)-(4-sec-butylphenyl)-methyl)guanidine;

N-(5-acenaphthyl)-N′-((4-tert-butylphenyl)-(4-sec-butylphenyl)-methyl)-N-methylguanidine;

N-(5-acenaphthyl)-N′-((4-tert-butylphenyl)-(4-sec-butylphenyl)-methyl)-N′-methylguanidine;

N-(5-acenaphthyl)-N′-((4-tert-butylphenyl)-(4-sec-butylphenyl)-methyl)-N,N′-dimethylguanidine;

N-(4-butoxyphenyl)-N,N′-bis(4-tert-butylbenzyl)guanidine;

N-(4-butoxyphenyl)-N,N′-bis(4-tert-butylbenzyl)-N-methylguanidine;

N-(4-butoxyphenyl)-N,N′-bis(4-tert-butylbenzyl)-N′-methylguanidine;

N-(4-butoxyphenyl)-N,N′-bis(4-tert-butylbenzyl)-N,N′-dimethylguanidine;

and pharmaceutically acceptable salts of said compounds.

Particularly preferred R substituent groups of compounds of Formula IV,as that formula is defined above, include halo, alkyl, alkoxy,benzyloxy, aminoalkyl, alkylthio, alkylsulfinyl, alkylsulfono, alkenyland alkynyl. Further preferred is where R¹ is carbocyclic aryl,particularly substituted or unsubstituted phenyl, naphthyl oracenaphthyl. Alkyl including methyl, ethyl and propyl are preferred R²or R³ groups.

Specifically preferred compounds of Formula IV include:

N,N′-di-(4-sec-butylphenyl)guanidine;

N,N′-di-(4-sec-butylphenyl)-N-methylguanidine;

N,N′-di-(4-sec-butylphenyl)-N,N′-dimethylguanidine;

N-(2-naphthyl)-N′-(4-isopropylphenyl)guanidine;

N-(2-naphthyl)-N′-(4-isopropylphenyl)-N-methylguanidine;

N-(2-naphthyl)-N′-(4-isopropylphenyl)-N′-methylguanidine;

N-(2-naphthyl)-N′-(4-isopropylphenyl)-N,N′-dimethylguanidine;

N,N′-bis(4-tert-butylphenyl)guanidine;

N,N′-bis(4-tert-butylphenyl)-N-methylguanidine;

N,N′-bis(4-tert-butylphenyl)-N′-methylguanidine;

N,N′-bis(4-tert-butylphenyl)-N,N′-dimethylguanidine;

N-(4-sec-butylphenyl)-N′-(2,3,4-trichlorophenyl)guanidine;

N-(4-sec-butylphenyl)-N′-(2,3,4-trichlorophenyl)-N-methylguanidine;

N-(4-sec-butylphenyl)-N′-(2,3,4-trichlorophenyl)-N′-methylguanidine;

N-(4-sec-butylphenyl)-N′-(2,3,4-trichlorophenyl)-N,N′-dimethylguanidine;

N-(4-methoxy-1-naphthyl)-N′-(2,3,4-trichlorophenyl)guanidine;

N-(4-methoxy-1-naphthyl)-N′-(2,3,4-trichlorophenyl)-N-methylguanidine;

N-(4-methoxy-1-naphthyl)-N′-(2,3,4-trichlorophenyl)-N′-methylguanidine;

N-(4-methoxy-1-naphthyl)-N′-(2,3,4-trichlorophenyl)-N,N′-dimethylguanidine;

N,N′-bis-(4-sec-butylphenyl)-2-iminopyrimidazolidine;

N,N′-bis(3-biphenyl)guanidine;

N,N′-bis(3-biphenyl)-N-methylguanidine;

N,N′-bis(3-biphenyl)-N′-methylguanidine;

N,N′-bis(3-biphenyl)-N,N′-dimethylguanidine;

N,N′-di-(3-tert-butylphenyl)-N-methylguanidine;

N,N′-di-(3-tert-butylphenyl)-N′-methylguanidine;

N,N′-di-(3-tert-butylphenyl)-N,N′-dimethylguanidine;

N,N′-bis-(4-methoxy-1-naphthyl)guanidine;

N,N′-bis-(4-methoxy-1-naphthyl)-N-methylguanidine;

N,N′-bis-(4-methoxy-1-naphthyl)-N′-methylguanidine;

N,N′-bis-(4-methoxy-1-naphthyl)-N,N′-dimethylguanidine;

N,N′-bis-(3-sec-butylphenyl)guanidine;

N,N′-bis-(3-sec-butylphenyl)-N-methylguanidine;

N,N′-bis-(3-sec-butylphenyl)-N′-methylguanidine;

N,N′-bis-(3-sec-butylphenyl)-N,N′-methylguanidine;

N,N′-bis(4-n-butylphenyl)guanidine;

N,N′-bis(4-n-butylphenyl)-N-methylguanidine;

N,N′-bis(4-n-butylphenyl)-N′-methylguanidine;

N,N′-bis(4-n-butylphenyl)-N,N′-dimethylguanidine;

N,N′-(sec-butylphenyl)-N′-(n-pentyl)guanidine;

N,N′-bis(3-benzyloxyphenyl)guanidine;

N,N′-bis(3-benzyloxyphenyl)-N-methylguanidine;

N,N′-bis(3-benzyloxyphenyl)-N,N′-dimethylguanidine;

N,N′-bis(4-benzyloxyphenyl)guanidine;

N,N′-bis(4-benzyloxyphenyl)-N-methylguanidine;

N,N′-bis(4-benzyloxyphenyl)-N,N′-dimethylguanidine;

N-(3-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)guanidine;

N-(3-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)-N-methylguanidine;

N-(3-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)-N′-methylguanidine;

N-(3-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)-N,N′-dimethylguanidine;

N,N′-bis-(4-tert-butylphenyl)-2-iminopyrimidazolidine;

N,N′-bis-(4-pentylphenyl)-2-iminopyrimidazolidine;

N,N′-bis-(4-hexylphenyl)-2-iminopyrimidazolidine;

N,N′-bis-(naphthyl)-2-iminopyrimidazolidine;

N,N′-bis-(5-acenaphthyl)-2-iminopyrimidazolidine;

N,N′-bis-(tetralinyl)-2-iminopyrimidazolidine;

and pharmaceutically acceptable salts of said compounds.

Specifically preferred compounds of Formula V, as defined above,include:

N-(5-acenaphthyl)-N′-(1,2,3,4-tetrahydroquinolinyl)guanidine;

N-(5-acenaphthyl)-N′-(1,2,3,4-tetrahydroquinolinyl)-N-methylguanidine;

N-(5-acenaphthyl)-N′-(1,2,3,4-tetrahydroquinolinyl)-N′-methylguanidine;

N-(5-acenaphthyl)-N′-(1,2,3,4-tetrahydroquinolinyl)-N,N′-dimethylguanidine;

N-(3-acenaphthyl)-N′-(indolinyl)guanidine;

N-(3-acenaphthyl)-N′-(indolinyl)-N-methylguanidine;

N-(3-acenaphthyl)-N′-(indolinyl)-N′-methylguanidine;

N-(3-acenaphthyl)-N′-(indolinyl)-N,N′-methylguanidine;

N-(5-acenaphthyl)-N′-(piperonyl)guanidine;

N-(5-acenaphthyl)-N′-(piperonyl)-N-methylguanidine;

N-(5-acenaphthyl)-N′-(piperonyl)-N′-methylguanidine;

N-(5-acenaphthyl)-N′-(piperonyl)-N,N′-dimethylguanidine;

and pharmaceutically acceptable salts of such compounds.

The invention also includes the following compounds, particularly foruse in the methods of treatm nt disclosed herein:

N-(2-naphthyl)-N′-(2-adamantyl)guanidine;

N-(2-naphthyl)-N′-(2-adamantyl)-N-methylguanidine;

N-(2-naphthyl)-N′-(2-adamantyl)-N′-methylguanidine;

N-(2-naphthyl)-N′-(2-adamantyl)-N,N′-dimethylguanidine;

N,N′-bis-(5-indanyl)-guanidine;

N,N′-bis(6-benz[cd]indolinyl-2[1H]-one)guanidine;

and pharmaceutically acceptable salts thereof.

Other specifically preferred compounds of the invention, including ofthe Formulas I-V above, include the following and are particularlypreferred for use in the methods of treatment disclosed herein:

N-(3-sec-butylphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(3-tert-butylphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(3-pentoxyphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(5-acenaphthyl)-N-(4-benzyloxybenzyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-benzyloxybenzyl)guanidine;

N-(4-benzyloxyphenyl)-N-(4-benzyloxybenzyl)guanidine;

N-(5-acenaphthyl)-N-(3-benzyloxybenzyl)guanidine;

N-(4-isopropylphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(4-benzyloxyphenyl)-N-(4-tert-butylbenzyl)guanidine;

N-(4-hexylphenyl)-N-(4-tert-hexylbenzyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-t-butylbenzyl)-N′-pyrrolidinylguanidine;

N-(4-sec-butylphenyl)-N-(4-t-butylbenzyl)-N′-(4-thiomorpholinyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-piperidinylguanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-morpholinyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-propylpiperidinyl)guanidine;

N-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)-N′-(4-piperidinyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-benzylpiperidinyl)guanidine;

N-(4-benzyloxyphenyl)-N-(4-tert-butylbenzyl)-N′-(4-morpholinyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(1,2,3,4-tetrahydroisoquinolinyl)guanidine;

N-(3-butoxy-4-methoxyphenyl)-N-(4-tert-butylbenzyl)-N′-(4-morpholinyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(3,5-dimethyl-4-morpholinyl)guanidine;

N-(4-tert-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-sec-butylphenyl)-N′-(methyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-sec-butylphenyl)-N′-(methyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(phenyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-chlorophenyl)guanidine;

N-(4-butoxylphenyl)-N-(4-tert-butylbenzyl)-N′-(phenyl)guanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(phenyl)-N′-methylguanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(3,4-dichlorophenyl)guanidine;

N-(4-hexylphenyl)-N-(4-tert-hexylbenzyl)-N′-phenylguanidine;

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-benzyloxyphenyl)guanidine;

N,N′-bis-(4-tert-butylphenyl)-N,N′-dimethylguanidine

N-(4-benzyloxyphenyl)-N′-(4-tert-butylphenyl)guanidine;

N,N′-bis-(3-(1′-methyl-2′-phenyl)ethyl)guanidine;

N-methyl-N-4-benzyloxyphenyl-N′-(4-tert-butylphenyl)guanidine;

N,N′-bis-(4-hexylphenyl)guanidine;

N-(3-(1-(4′-ethoxy)benzyl)phenethyl)-N′-(4-tert-butylphenyl)guanidine;

N-(4-benzyloxyphenyl)-N′-methyl-N-(4-tert-butylphenyl)guanidine;

N-(3-(4-tert-butylbenzyloxy)phenyl)-N′-(4-tert-butylphenyl)guanidine;

N-(3-(1′-benzylbutyl)phenyl)-N′-(4-tert-butylphenyl)guanidine;

N,N′-bis-(4-butylphenyl)-N-methylguanidine;

N,N′-bis-(4-tert-butylphenyl)-N,N′-dimethylguanidine;

N-(3-naphthaloxyphenyl)-N′-(4-tertbutylphenyl)guanidine;

N-(4-benzyloxyphenyl)-N′-(4-butylphenyl)guanidine;

N,N′-bis-(4-butylphenyl)-N-butylguanidine;

N-3-(benzyloxymethyl)phenyl-N′-(4-tert-butylphenyl)guanidine;

N-(3,4-bis-butyloxyphenyl)-N′-(4-tert-butylphenyl)guanidine;

N-(3-benzyloxy)phenyl-N′-(4-tert-butylphenyl)guanidine;

N,N′-bis-(3-butoxy-4-methoxy)phenylguanidine;

N-(4-benzyloxyphenyl)-N-methyl-N′-(4-butylphenyl)guanidine;

N-(4-benzyloxyphenyl)-N′-methyl-N′-(4-butylphenyl)guanidine;

N,N′-bis-(6-tetralinyl)guanidine;

N-(6-tetralinyl)-N′-(4-tert-butylphenyl)guanidine;

N-(5-acenaphthyl)-N′-(6-benzothiozolyl)guanidine;

N-(5-acenaphthyl)-N′-(6-N-benzylindolinyl)guanidine;

N-(5-acenaphthyl)-N′-(4-benzo-2,1,3-thiadizaole)guanidine;

N-(5-acenaphthyl)-N′-[4-(6-methyl-benzothiazole)phenylguanidine;

N-(5-acenaphthyl)-N′-(1-benz[cd]indolinyl)guanidine;

N-(5-acenaphthyl)-N′-(6-benz[cd]indo-2[1H]-one)guanidine;

N-(4-butoxyphenyl)-N′-(4-chlorophenylethyl)guanidine;

N-(4-benzyloxyphenyl)-N,N′-diphenylguanidine;

N-(4-benzyloxyphenyl)-N′-benzyl-N′-phenylguanidine;

N-(3-benzyloxyphenyl)-N′-(4-thiobenzylphenyl)guanidine;

N,N′-bis(4-(phenylthio)phenyl)guanidine;

N,N′-bis(3-(phenylthio)phenyl)guanidine;

N-(5-acenaphthyl)-N′-(2-phenylethyl)guanidine;

N-(5-acenaphthyl)-N′-(3-butoxypropyl)guanidine;

N,N′-bis(2,2-diphenylethyl)guanidine;

N-(4-butoxyphenyl)-N′-(4-chlorophenylethyl)guanidine;

N-(4-butoxyphenyl)-N-(4-chlorobenzhydryl)guanidine;

(5-acenaphthyl)-N′-(phenethyl)-N′-benzylguanidine;

N-4-benzyloxyphenyl)-N′-(3-benzyloxyphenyl)-N′-(4-chlorobenzyl)guanidine;

N,N′-bis(4-benzyloxyphenyl)-N′-methylguanidine;

N-(4-benzyloxyphenyl)-N′-(3-benzyloxyphenyl)-N′-(4-chlorobenzyl)guanidine;

N-(3-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)-N′-phenylguanidine;

N-(4-sec-butylphenyl)-N′-(4-isopropoxyphenyl)-N′-phenylguanidine;

N-(4-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)-N′-phenylguanidine;

N,N′-bis(3-octyloxyphenyl)guanidine;

N,N′-bis(4-butoxyphenyl)guanidine;

N,N′-bis(4-phenoxyphenyl)guanidine;

N-(3-benzyloxyphenyl)-N′-(4-phenoxyphenyl)guanidine;

N-(3-benzyloxyphenyl)-N′-(4-phenylazophenyl)guanidine;

N,N′-bis(3-benzyloxyphenyl)-N′-methylguanidine;

N-(4-benzyloxphenyl)-N′-(4-benzyloxyphenyl)-N′-methylguanidine;

N-(4-butoxyphenyl)-N′-(4-isopropoxyphenyl)guanidine;

N-N′-bis(4-(1-hydroxybutyl)phenyl)guanidine;

N-(4-butoxyphenyl)-N′-(3-methoxyphenyl)-N′-phenylguanidine;

N-(4-secbutylphenyl)-N′-phenyl-N′-(4-(2-isopropoxy)phenyl)guanidine;

N-(4-n-butoxyphenyl)-N′-(2-(4-chlorophenyl)ethyl)guanidine;

and pharmaceutically acceptable salts thereof.

Compounds of the invention can be prepared by reaction of an amine,typically an amine salt such as an amine hydrochloride, with a preformedalkyl or aryl cyanamide (see S. R. Safer, et al., J. Org. Chem., 13:924(1948)) or the corresponding N-substituted alkyl or aryl cyanamide. Seealso G. J. Durant, et al., J. Med. Chem., 28:1414 (1985); C. A.Maryanoff, et al., J. Org. Chem., 51:1882 (1986); M. P. Kavanaugh, etal., Proc. Natl. Acad. Sci. USA, 85:2844-2848 (1988); E. Weber, et al.,Proc. Natl. Acad. Sci. USA, 83:8784-8788 (1986); H. W. J. Cressman, Org.Syn. Coll., 3:608-609 (1955); International Applications WO 91/12797 andPCT/US92/01050.

More particularly, synthesis of N,N-disubstituted compounds of Formula Ican be achieved by condensation of a disubstituted amine with cyanamide.For example, a disubstituted amine is prepared having the desiredsubstituents R and R¹ (as those substituents are defined in Formula Iabove), e.g., by condensation of a primary amine of the formula R—NH₂with a compound of the formula R¹ wherein L is a leaving group and R andR¹ are as defined above for Formula I. Suitable reaction conditions canbe readily determined based on the constituents employed. For example, abenzylhalide is suitably added to an arylamine at reduced temperature inthe presence of a tertiary amine such as triethylamine and, afteraddition completion, the mixture is stirred at room temperature forabout 15 hours. The resulting secondary amine can be purified byconventional means such as chromatography and then reacted with asuitable acid such as methanesulfonic acid to form the amine salt. Theamine salt is reacted with a large molar excess of cyanamide in asuitable solvent such as methanol for a time and temperature sufficientto form the N,N-disubstituted guanidine.

Synthesis of symmetrical N,N′-disubstituted guanidines of the inventioncan be typically achieved by directly reacting two equivalents of theamine with one equivalent of cyanogen bromide in suitable solvent suchas ethanol as depicted in “Method A” of Scheme 1 below. UnsymmetricalN,N′-disubstituted guanidines can be prepared by reacting a substitutedcyanamide such as aryl cyanamides with the appropriate amine hydrohalidesalts in suitable solvent such as refluxing chlorobenzene or toluene asdepicted in “Method B” of Scheme 1 below. The requisite cyanamides canbe synthesized from the corresponding amines by treatment with cyanogenbromide in suitable solvent such as ether.

N,N,N′-tri-substituted or N,N,N′,N′-tetra-substituted guanidines of theinvention can be synthesized (Scheme II below, Method C and Drespectively) by reacting a substituted cyanamide such as aN-alkyl-N-arylcyanamide with an appropriate amine hydrohalide salt in asuitable solvent such as refluxing chlorobenzene or toluene. Thestarting cyanamides can be synthesized, e.g., by an alkylation of anarylcyanamide with sodium hydride/alkyl halide in suitable solvent suchas tetrahydrofuran.

Appropriate substituted amine and cyanamide reagents are available orcan be prepared by recognized procedures. A nitro acenaphthyl derivativehaving one or more additional ring substituents can be prepared asdescribed by M. D. Varney, et al., J. Med. Chem., 35:671 (1992). Such asubstituted nitro acenaphthyl derivative can be reduced to thecorresponding amine by hydrogenation, and the amine reacted with BrCN asdiscussed above. For preparation of other acenaphthyl derivatives havingan amine or amine precursor group and one or more additional ringsubstituents, see V. N. Komissarov, Zh. Org. Khim., 26(5): 1106-10(1990); L. Skulski, et al., Pol. J. Chem., 55(9): 1809-24 (1981); A. F.Pozharskii, Isobret. Prom. Obraztsy, Tovarnye Znaki, (3), 96-7 (1982);J. P. Li, et al., US 78-890736 (1978); N. S. Vorozhtsov, Zh. Org. Khim.,8(2): 353-7 (1972); J. Wolinski et al., Rocz. Chem., 44(9): 1721-31(1970); A. P. Karishin, et al., Zh. Obshch. Khim., 39(9): 2098-101(1969); and V. V. Mezheritskii, et al., Zh. Org. Khim., 27(10): 2198-204(1991).

Compounds of Formula IV where R² and R³ taken together form asubstituted or unsubstituted alkylene linkage of from 2 to about 6carbon atoms can be prepared as exemplified by the procedure disclosedin Example 8 which follows. Thus, as clearly understood by those skilledin the synthesis arts, an appropriate N-substituted diaminealkylene issuitably reacted with cyanogen bromide in an appropriate solvent such asan alcohol and the reaction conducted at a temperature and for a timesufficient to carry out the reaction. The cyclic reaction product can besuitably purified by conventional techniques if desired, such as bychromatography.

As discussed above, the substituted guanidines of the invention areuseful for a number of therapeutic applications, including treatment ofthose diseases that result from modulation of a particularneurotransmitter system that can be counteracted by one or more of thesubstituted guanidines of the invention. As mentioned above, modulationof neurotransmitter release involves either the inhibition ofneurotransmitter release, the potentiation of neurotransmitter release,or the increase or decrease of the time course of neurotransmitterrelease from neuronal tissue. Neurotransmitters which may be modulatedby compounds of the invention include, but are not limited to thoseneurotransmitters identified above. One of ordinary skill in the art canselect those compounds which are effective or particularly effectivemodulators of neurotransmitter release using the procedures disclosedherein, or in the literature such as PCT/US92/01050, with no more thanroutine experimentation. For example, compounds for the prevention ofneuronal death in brain ischemia can be evaluated in vivo in one or morevariations of the rat middle cerebral artery occlusion model. Suchmodels are generally considered to be particularly predictive ofneuroprotective efficacy in stroke [Ginsberg, et al., Stroke,20:1627-1642 (1989)]. Efficacy of compounds of the Invention also may beassessed in the 4-vessel occlusion model of global ischemia [Pulsinelli,et al., Stroke:19:913-941 (1988)].

In particular, the invention provides methods for treatment and/orprophylaxis of neurological conditions such as epilepsy,neurodegenerative conditions and/or nerve cell death resulting from,e.g., hypoxia, hypoglycemia, brain or spinal chord ischemia, brain orspinal chord trauma, stroke, heart attack or drowning. Typicalcandidates for treatment include heart attack, stroke, brain or spinalcord injury patients, patients undergoing major surgery where brainischemia is a potential complication and patients such as diverssuffering from decompression sickness due to gas emboli in the bloodstream.

The invention also provides methods to treat and/or prevent variousneurodegenerative diseases of a subject such as an animal, particularlya human, by administering a therapeutically effective dose of one ormore compounds of the invention. Typical neurodegenerative diseases thatcan be treated and/or prevented include Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer'sdisease, Down's Syndrome, Korsakoff's disease, olivopontocerebellaratrophy, HIV-induced dementia and blindness, multi-infarct dementia ordiabetic neuropathy. As disclosed by Dreyer et al., Science, 248:364-367(1990), gp120 neurotoxicity is associated with increased levels of Ca²⁺which are apparently mediated by Ca channels and blocked bydihydropyridine Ca channel antagonists. Though again not wishing to bebound by theory, compounds of the invention should have utility intreating HIV-induced dementia and blindness by means of preventing therelease of excessive glutamate.

As noted above the invention provides methods of treating Korsakoff'sdisease, a chronic alcoholism-induced condition, comprisingadministering to a subject including a mammal, particularly a human, oneor more compounds of the invention in an amount effective to treat thedisease. Pretreatment of animals with the NMDA antagonist MK-801 (MerckIndex, monograph 3392, 11th ed., 1989) markedly attenuates the extent ofcell loss, hemorrhages and amino acid changes in a rat model ofKorsakoff's disease. See P. J. Langlais, et al., Soc. Neurosci. Abstr.,14:774 (1988). Therefore, compounds of the invention have utility forthe attenuation of cell loss, hemorrhages and amino acid changesassociated with Korsakoff's disease.

At least some compounds of the invention will have utility in treatingor preventing conditions treatable by the blockage of voltage-activatedsodium ion-channels. Accordingly, the invention provides methods forblockage of voltage-activated sodium channels of neuronal cells,particularly mammalian cells such as human neuronal cells, comprisingthe administration to the cells of an effective amount of a compound ofthe invention, particularly by such administration to a mammal in needof such treatment. Conditions that can be treated by blockage of sodiumchannels will include, e.g., epilepsy. The invention also providesmethods of for blockage of sodium channels of mammalian smooth orskeletal muscle cells, comprising administering to such cells aneffective amount of one or more a compounds of the invention. Suchmethods will also be useful, e.g., for therapy of a mammal such as ahuman having or susceptible to paramyotonia or hyperkalemic periodicparalysis [See Cannon, S. C. et al., Neuron, 10:317-326 (1993)].

Moreover, some compounds of the invention will block both sodiumchannels as well as presynaptic calcium channels. This dual action maybe particularly desirable for neuroprotective therapies [Kucharczyk, J.et al., Radiology, 179:221-227 (1991)].

It has been reported that NMDA antagonists which do not cross theblood/brain barrier may be used to alleviate certain undesirable sideeffects of cancer chemotherapy, e.g. nausea and emesis [A. Fink-Jensenet al., Neurosci. Lett., 137(2):173 (1992)]. See also Price, M. T., etal., Soc. NeuroSci. Abstr., 16:377, abstr. 161.16 (1990). These actionsof NMDA antagonists are presumably mediated by blockade of thepostsynaptic activity of glutamate released from neurons of theperipheral nervous system. Again without wishing to be bound by theory,this indicates that compounds which block the release of glutamate willbe useful for this therapeutic indication. Compounds of the invention,particularly those compounds that are charged such as in the form of apharmaceutically acceptable salt, and those compounds that are otherwisehydrophilic such as compounds that comprise one or more polarfunctionalities e.g. carboxy, zig amino, hydroxy and the like, may havecomparatively limited ability to cross the blood brain barrier. It isthus believed that compounds of the invention, especially charged orotherwise hydrophilic compounds of the invention with limited bloodbrain barrier permeability, will be clinically useful to ameliorate theside effects associated with chemotherapy, particularly cancerchemotherapy, that may be experienced by a mammal, particularly a humanreceiving such chemotherapy. The compound of the invention would betypically administered to the subject in coordination with thechemotherapy regime.

Compounds of the invention may be used in therapy in conjunction withother medicaments. For example, for treatment of a stroke victim, one ormore compounds of the invention may be suitably administered togetherwith a pharmaceutical targeted for interaction in the blood clottingmechanism such as streptokinase, TPA and urokinase. See VonKummer, R. etal., Stroke, 23:646-652 (1992); Sereghy, T. et al., Stroke, 24:1702-1708(1993).

Compounds of the invention will be useful for treatment of secretorydisorders, particularly in view of the demonstrated ability of thecompounds to block Ca channels which are identical or closely related tothose which regulate secretion. The invention thus includes methods forblocking voltage-activated calcium channels of mammalian secretory cellswhich comprises administering to such cells a blockage-effective amountof a compound of the invention. The invention further provides methodsfor treatment of a disease in which the pathophysiology of the disorderinvolves inappropriate or excessive cellular secretion of acatecholamine, a growth factor or precursor thereof (including thosegrowth factors specifically discussed infra), a hormone or precursorthereof (including those hormones specifically discussed infra) or amember of the neuregulin family of proteins including glial growthfactors, the heregulins and the neu differentiation factors. Such amethod will be particularly useful for treating a mammal such as a humansuffering from or susceptible to hypersecratory disorders discussedbelow.

More particularly, compounds of the invention could be used in treatmentof a hypersecretory disorder such as pheochromocytoma, which is adisorder resulting from the presence of a tumor of the chromaffin cellsin the adrenal medulla [Bravo, E. L. and Gifford, R. W. (1984) New Eng.J. Med. 311: 1298-1300]. This disorder is characterized by thehypersecretion of catecholamines, resulting in hypertension which may beparoxysmal and associated with attacks of palpitation, headache, nausea,breathing difficulty, and anxiety. Compound(s) of the invention alsocould be used in treatment of pancreatitis, which is an inflammation ofthe pancreas leading to hypersecretion of hormones and enzymes from theacinar cells of the pancreas, among them hormones such as vasoactiveintestinal peptide (VIP) and insulin; digestive enzymes and theirinactive precursors, among them lipases and proteases,deoxyribonucleases, ribonucleases, and amylase [Greenberger, N. J. etal. Harrison's Principles of Internal Medicine, 11th Ed., New York,McGraw-Hill, pp. 1372-1380 (1987)]. In severe cases of pancreatitis,autodigestion of the pancreas by the hypersecretion and subsequentactivation of said digestive enzymes can be fatal [Greenberger, N. J. etal., ibid]. For these and other indications mediated by hypersecretoryactivity outside the central nervous system, compounds of the invention,particularly those which are charged and/or hydrophilic or otherwisehave limited blood/brain barrier permeability should be clinicallyuseful upon systemic and/or local administration.

Certain hypersecretory disorders may result from abnormal activity ofcells within the central nervous system, among them cells of thepituitary gland, also termed the hypophysis, located at the base of thebrain. Secretion of hormones and related substances from cells of theadenohypophysis is regulated by releasing factors, primarily thosesecreted by the hypothalamus [Cooper, P. E. et al., Diseases of theNervous System: Clinical Neurobiology, eds, Saunders, Philadelphia, pp.567-583 (1992)]. Substances secreted by the adenohypophysis includegrowth hormone, prolactin, thyroid stimulating hormone (TSH), andadrenocorticotrophic hormone (ACTH). Hypersecretion of these substancesfrom the pituitary can lead to a variety of disorders of growth (e.g.acromegaly due to hypersecretion of growth hormone) and metabolism (e.g.secondary hyperthyroidism triggered by hypersecretion of TSH, andCushing's disease, which results from excessive secretion by thepituitary of precursor peptides containing ACTH) [see Cooper, P. E. etal. Ibid.]. These disorders are often due to benign tumors of thepituitary secretory cells. Compounds of the invention, particularlythose that are relatively hydrophobic and/or by some means penetrate theblood/brain barrier, should have utility for treatment of such disordersby suitable administration to a subject, particularly a human. In someinstances pharmacotherapy with compounds of the invention may obviatethe necessity and attendant risk of neurosurgery performed for thepurpose of removing such benign tumors. As referred to above,hydrophobic compounds of the invention would include those compoundsthat do not comprise highly polar moieties such as carboxy and the like.

Compounds of the invention also may be used in treatment of disordersinvolving hypersecretion of substances produced by the hypothalamus suchas diabetes insipidus, which may be caused by hypersensitivity to, orexcessive release of, AVP. AVP is a peptide synthesized in and releasedfrom neurons of the supraoptic and paraventricular nuclei of thehypothalamus [see Copper, P. E. et al., Diseases of the Nervous System:Clinical Neurobiology, eds, Saunders, Philadelphia, pp. 567-583 (1992)].A current means of treatment of diabetes insipidus is surgicaldestruction of most of the cells in the supraoptic nucleus.Pharmacotherapy with compounds of the invention could in at least someinstance obviate the need for such neurosurgery.

The pituitary has been indicated to secrete growth factors. Evidenceshows a family of proteins, termed glial growth factors (“GGF”'s), to bea group of such growth factors secreted by the pituitary. GGF's aremitogenic for myelin-forming Schwann cells, and as such may play animportant role in development and regeneration of the nervous system[Marchionni et al., Nature, 362:312-318 (1993)]. Bovine pituitary glandshave been identified as an enriched source of GGF's, and a GGF of M_(r)31,000 has been purified from bovine pituitary [Lemke, G. E. et al., J.Neurosci., 4:75-83 (1984)]. Multiple molecular forms of GGF may besecreted from the pituitary, either in active form or as precursors.GGF's from bovine pituitary extracts can be resolved into at least 3activities with different molecular masses: GGF-I (34,000), GGFII(59,000), and GGFIII (45,000) [Goodearl et al., J. Biol Chem.,268:18095-18102 (1993)]. GGF's are structurally related to members of afamily of proteins which are known to activate the p185^(vrB2) receptorkinase, including the heregulins [Holmes, W. E. et al., Science,256:1205-1210 (1992)], and neu differentiation factor [Wen, D. et al.,Cell, 69:559-572 (1992)].

While the precise role of GGF's and the aforementioned related proteinsin the development, maintenance, and/or repair of the nervous system andmuscle has yet to be elucidated, and the mechanism of secretion of GGF'sand related molecules has yet to be defined, existing evidence indicatesthat pathophysiological circumstances may arise in which it may bedesirable to regulate the secretion of GGF's and related proteins fromthe pituitary and/or other secretory sites. One such circumstance may bediseases that involve the deterioration of nerve, for example diabeticneuropathy [Duchen, L. W. (1983) in Autonomic Failure: A Textbook ofClinical Disorders of the Nervous System, Bannister, R., ed., N.Y.,Oxford Univ. Press; Foster, D. W. (1987) in Harrison's Principles ofInternal Medicine, 11th Ed., New York, McGraw-Hill, pp. 1788-1795], orthe deterioration of muscle, among them muscular dystrophies [Brooke, M.H. (1985) A Clinician's View of Neuromuscular Disease, 2nd ed.,Baltimore, Williams and Wilkins; Huges, S. M., and Blau, H. M. (1990)Nature 345: 350-352]. Compounds of the invention should have therapeuticutility in treating such disorders involving the deterioration of nerveor muscle. Without wishing to be bound by theory, it is believed thatcompounds of the invention will have utility in treating such disordersby modulating the exocytosis from the cells in which they aresynthesized of GGF's, other members of the neuregulin family, and otherfactors secreted into the blood which are involved in development,maintenance, or repair of nerve and/or muscle.

The aforementioned ability of compounds of the invention to block Cachannels which are identical or closely related to those which regulatecardiovascular function, as demonstrated in the examples which follow,indicate that compounds of the invention will find utility in therapy ofcardiovascular disorders. Among the disorders currently known to betreatable by inhibitors of L-type Ca channels such as verapamil,diltiazem, and nifedipine are hypertension, angina pectoris, cardiacarrhythmias. As shown in Example 148, a subset of compounds of theinvention show equal or greater potency for block of L-type Ca channelswhen compared with the ability of verapamil or diltiazem to block saidchannels using the same assay protocol.

The aforementioned ability of compounds of the invention to block Nachannels which are closely related to those which regulatecardiovascular function, as shown in Example 149, infra, indicate thatcompounds of the invention will find utility in therapy ofcardiovascular disorders treatable by blockers of Na channels. Theinvention thus includes methods for blocking voltage-activated sodiumchannels of mammalian cardiac cells comprising administration to suchcells a blockage-effective amount of one or more compounds of theinvention. A major indication for such Na channel blockers is cardiacarrhythmias, which are currently treated by blockers of Na channels,among them quinidine, procainamide, lidocaine, and diphenylhydantoin(phenytoin). Among the cardiac arrhythmias successfully treatable bysaid Na channel blockers are ventricular tachycardia; ventricularpremature depolarizations; digitalis-induced atrial tachycardia andatrial and ventricular arrhythmias; paroxysmal supraventriculartachycardia; atrial fibrillation; and prophylaxysis against thedevelopment of supraventricular arrhythmias (see Bigger, J. T. et al.,The Pharmacological Basis of Therapeutics, 7th Ed., eds., New York,MacMillan, pp. 748-783 (1985)). Accordingly, compounds of the inventionshould find utility in treatment of cardiac arrhythmias treatable byblockers of cardiac Na channels. Compounds of the invention should findutility in treatment of hypertension and/or angina pectoris treatable byblockers of cardiac Na channels. For these and other indicationstreatable by blocking cardiac Na channel activity, compounds of theinvention, particularly those which are charged and/or hydrophilic andotherwise do not cross the blood/brain barrier, are believed to beclinically useful upon systemic and/or local administration.

Some cardiac arrhythmias, among them paroxysmal supraventriculartachycardia and other supraventricular arrhythmias, are treatable byboth blockers of cardiovascular L-type channels and by blockers ofcardiac Na channels. Compounds of the invention with dual actionsagainst Na channels and Ca channels (such asN-(5-acenaphthyl)-N-(4-iso-propylbenzyl) guanidine andN-(4-methoxynaphthyl)-N′-(2,3,4-trichlorophenyl)guanidine), should thushave particular utility in treatment of said arrhythmias.

As discussed above, compounds of the invention also will be useful fortreatment of chronic pain and as a local anesthetic.

The compounds of this invention can be administered to a subject such asa human intranasally, orally or by injection, e.g., intramuscular,intraperitoneal, subcutaneous or intravenous injection, or bytransdermal, intraocular or enteral means. The optimal dose can bedetermined by conventional means including the assays described in theexamples which follow. Guanidines of the invention are suitablyadministered to a subject in the protonated and water-soluble form,e.g., as a pharmaceutically acceptable salt of an organic or inorganicacid, e.g., hydrochloride, hydrobromide, sulfate, hemi-sulfate,mesylate, gluconate, phosphate, nitrate, acetate, oxalate, citrate,maleate, etc., prepared by procedures such as those disclosed in theexamples which follow.

The compounds of this invention can be employed, either alone or incombination with one or more other therapeutic agents as discussedabove, as a pharmaceutical composition in mixture with conventionalexcipient, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral, enteral or intranasalapplication which do not deleteriously react with the active compoundsand are not deleterious to the recipient thereof. Suitablepharmaceutically acceptable carriers include but are not limited towater, salt solutions, alcohol, vegetable oils, polyethylene glycols,gelatin, lactose, amylose, magnesium stearate, talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like which do not deleteriously react withthe active compounds.

For parenteral application, particularly suitable are solutions,preferably oily or aqueous solutions as well as suspensions, emulsions,or Implants, including suppositories. Ampules are convenient unitdosages.

For enteral application, particularly suitable are tablets, dragees orcapsules having talc and/or carbohydrate carrier binder or the like, thecarrier preferably being lactose and/or corn starch and/or potatostarch. A syrup, elixir or the like can be used wherein a sweetenedvehicle is employed. Sustained release compositions can be formulatedincluding those wherein the active component is protected withdifferentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc.

Intravenous or parenteral administration, e.g., sub-cutaneous,intraperitoneal or intramuscular administration are generally preferred.

Instances may arise in which site-specific drug-delivery methods wouldconstitute a preferred method of delivering compounds of the inventionto the tissue in need of therapy [see Tomlinson, E., Advanced DrugDelivery Reviews, 1:87-198 (1987)]. For example, in the case ofdisorders of muscle function originating from a pathophysiologicalcondition of Na channels of skeletal muscle, among them hyperkalemicperiodic paralysis, it may be desirable to microencapsulate compounds ofthe invention within delivery vehicles such as liposomes [Yagi, K.,Medical Applications of Liposomes, Japan Soc. Press, Tokyo (1986);Gregoriadis, G., ed. Liposome Technology, Vol. I-III, CRC press, Inc.,Cleveland (1984)], said liposomes containing a monoclonal antibodytargeted to specific antigens on or near the surface of the diseasedmuscle cells. Said method of drug delivery should result in selectivebinding of the liposomes to the target tissue, and release of thecompound of the invention near the abnormally functioning skeletalmuscle Na channels, where said compound will inhibit the persistentactivation of muscle Na channels which constitutes the molecularabnormality underlying the disease.

A targeted delivery method of one or more compounds of the inventionalso may be preferred for treatment of pheochromocytoma or anotherabnormality which results in hypersecretion of catecholamines into theblood. Because the Ca channels of chromaffin cells are closely relatedto those of nerve, cardiac cells, and muscle (Neher, E. et al., Neuron,10:21-30 (1993); Bean, B. P. Ann. Rev. Physiol., 51:367-384 (1989);Hess, P., Ann. Rev. Neurosci., 13:337-56 (1990)), systemicadministration of a compound of the invention at concentrationssufficient to block release of catecholamines from chromaffin cells mayproduce certain side effects resulting from block of, for example,neuronal and cardiovascular Ca channels. Accordingly, delivery ofcompounds of the invention to chromaffin cells may be enhanced and saidside effects reduced by their incorporation into liposomes containing amonoclonal antibody targeted to specific antigens on or near the surfaceof the chromaffin cells of the hypersecreting adrenal medulla.

This method of liposome-mediated drug targeting has been reported fordelivery of a variety of agents, to be used for indications such ascancer chemotherapy and destruction of tumors (e.g., Bassett, J. B. etal. J. Urol., 135:612-615 (1986)]. Suitable refinements of that methodas well as new methods for site-specific drug delivery will be usefulfor administration of compounds of the invention to a subject. Inparticular, appropriate methods for site-specific delivery of compoundsof the invention may include incorporation of said compounds intopolymer beads which afford slow site-specific release [Mathiowitz, E. etal., J. Controlled Release, 5:13-18 (1987)], and delivery to the targettissue by means of surgically implanted pumps.

It will be appreciated that the actual preferred amounts of activecompounds used in a given therapy will vary according to the specificcompound being utilized, the particular compositions formulated, themode of application, the particular site of administration, etc. Optimaladministration rates for a given protocol of administration can bereadily ascertained by those skilled in the art using conventionaldosage determination tests conducted with regard to the foregoingguidelines. In general, a suitable effective dose of one or morecompounds of the invention, particularly when using the more potentcompound(s) of the invention, will be in the range of from 0.5 to 500milligrams per kilogram bodyweight of recipient per day, preferably inthe range of 1 to 100 milligrams per kilogram bodyweight of recipientper day. The desired dose is suitably administered once daily, or inseveral sub-doses, e.g., 2 to 4 sub-doses, are administered atappropriate intervals through the day, or other appropriate schedule.Such sub-doses may be administered as unit dosage forms, e.g.,containing from 0.25 to 25 milligrams of compound(s) of the inventionper unit dosage, preferably from 0.5 to 5 milligrams per unit dosage.

Alternatively, compounds of the invention may be administeredcontinuously for a period of time, for example by an intravenousinfusion or by means of a suitably placed transdermal patchIncorporating and releasing compounds of the invention.

As disclosed above, suitably labeled compounds of the invention can beused to detect ion channel (e.g., Ca or Na) activity, which will serveto diagnosis certain human diseases as discussed herein. A compound ofthe invention may be suitably radiolabeled, e.g. with ¹²⁵I such as on anaryl ring of the compound, and the labeled compound administered to asubject and the subject then scanned for binding of the compound to ionchannels using an appropriate scanning tool. For example, single photonemission computed topography (“SPECT”) may be suitably employed todetected such binding. Suitable radiolabeled compounds of the inventionmay be prepared by known procedures. For example, a compound of theinvention having an aromatic group, such as phenyl, that has a bromo orchloro ring substituent can be employed in an exchange labeling reactionto provide the corresponding compound having an ¹²⁵I ring substituent.

As with prior guanidines such as those reported in U.S. Pat. No.1,411,713, the guanidines of the present invention should have utilityas rubber accelerators.

All documents mentioned herein are incorporated herein by reference intheir entirety.

The present invention will be further illustrated with reference to thefollowing examples which aid in the understanding of the presentinvention, but which are not to be construed as limitations thereof.

General Comments

In the following examples, all percentages reported herein, unlessotherwise specified, are percent by weight. All temperatures areexpressed in degrees Celsius.

Melting points were determined in open capillary tubes on aThomas-Hoover apparatus and are uncorrected. Thin-layer chromatographywas performed on Baker-flex 1B2-F silica gel plates. Guanidines werevisualized on TLC with 254-nM UV light or as a blue spot with bromcresolspray reagent (Sigma Chemical Co.). Preparative TLC was performed onAnaltech GF precoated silica gel (1000 μm) glass-backed plates (20×20cm). The IR, ¹H and ¹³C NMR spectra of all compounds were consistentwith their assigned structures. NMR spectra were recorded on VarianGemini 300 and the chemical shifts were reported in ppm (δ) relative tothe residual signal of the deuterated solvent (CHCl₃, δ 7.26; CHD₂OD, δ3.30). Infrared spectra were recorded in CHCl₃ (unless otherwise noted)on Perkin-Elmer model 1420. All new compounds were analyzed either forC, H, and N elemental analyses or for exact mass. Elemental analyseswere performed by either Galbraith Laboratories (Knoxville, Tenn.) orMHW Laboratories (Tuscon, Ariz.). High Resolution Mass spectra (HRMS)were recorded on a Finnegan MAT 90. HPLC were performed on a C18 reversephase column using 50:50 water:acetonitrile with 0.1% TFA as the mobilephase. BrCN was obtained from Aldrich Chemical Co., and was used asreceived. All starting amines were obtained from commercial sources andwere purified by standard procedures before use, or they were prepared,where noted, by published procedures. Chlorobenzene, ether (Et₂O) andtetrahydrofuran (THF) were anhydrous quality solvents (Sure Seal)supplied by Aldrich. All other solvents were reagent grade. Alkyl- andarylcyanamides were prepared as described above and according topublished procedures (e.g., PCT/US92/01050) by reaction of the amineswith BrCN in ether.

EXAMPLE 1 Preparation ofN-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

Part 1: Preparation of N-(4-sec-Butylphenyl)-4-tert-butylbenzylamine

A mixture of 4-sec-butylaniline (2.89 g, 20 mmol) and triethylamine (2.5g, 25 mmol) in toluene (100 mL) was stirred at 4° C. for 15 hours andprecipitates formed. The precipitates (triethylamine.HBr) were filteredout; the filtrate was concentrated to dryness. Then the crude reactionmixture was purified by column chromatography (SiO₂, hexane/CH₂Cl₂=5/1).N-(4-sec-butylphenyl)-4-tert-butylbenzylamine (4.5 g, an oil) wasobtained.

Part 2: Preparation of N-(4-sec-Butylphenyl)-4-tert-butylbenzylamine.HCl

To a solution of N-(4-sec-butylphenyl)-4-tert-butylbenzylamine (4.5 g)in diethylether (10 mL) was added ether at HCl solution at 4° C., thenthe reaction mixture was stirred at 25° C. for 10 minutes. The resultingsolution, was the evaporated and dried under vacuum to afford 4.7 g ofN-(4-sec-butylphenyl)-4-tert-butylbenzylamine.HCl.

Part 3: Preparation ofN-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

A mixture of N-(4-sec-butylphenyl)4-tert-butylbenzylamine.HCl (0.8 9,2.7 mmol) and cyanamide (2 g) in methanol was heated at 70° C. for 40hours. During the 40 hour period, another two portions of cyanamide (0.5g, each time) were added. The reaction did not go to completion; a smallpercentage of N-(4-sec-butylphenyl)-4-tert-butylbenzylamine.HCl remainedin the mixture. The crude product was purified by column chromatography(SiO₂, CH₂Cl₂/MeOH=9/1). Then the purified compound (a mixture of theguanidine and some cyanamide) dissolved in water (20 mL) was basified topH 14. The guanidine.free base was extracted with CH₂Cl₂ (20 mL, twotimes) and the combined extracts were concentrated. Finally, the pureN-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)guanidine was converted intoits HCl salt by methanolic HCl treatment. After drying under vacuum for15 hours, the pure product (0.6 g) was obtained as a white solid, mp:177-178° C.; TLC: R_(f)=0.4 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CD₃OD): δppm 7.39-7.12 (m, ArH, 8H), 4.90 (s, CH₂, 1H), 4.88 (s, CH₂, 1H), 2.63(m, CH, 1H), 1.57 (m, CH₂, 2H), 1.29 (s, CH₃, 9H), 1.21 (d, CH₃, 3H),0.80 (t, CH₃, 3H); HRMS: 337.2524 (337.2518 Calcd. for C₂₂H₃₁N₃); HPLC:99% pure.

EXAMPLE 2 Preparation ofN-5-Acenaphthyl)-N-(4-tert-butylbenzyl)guanidine

Part 1: Preparation of 5-Acenaphthylamine

A mixture of 5 and 3-nitroacenaphthene was reduced with Pd/C in ethylacetate under hydrogen at 40 psi pressure and the resulting amines wereseparated by recrystallization from cyclohexane/ethyl acetate.

Part 2: Preparation of N-(5-Acenaphthyl)-4-tert-butylbenzylamine

A mixture of 5-acenaphthylamine (1.0 g, 6 mmol) and triethylamine (0.76g, 7.5 mmol) in toluene (50 mL) was stirred at 4° C., and4-tert-butylbenzyl-bromide (1.36 g, 6 mmol) was added in slowly. Thereaction mixture was stirred at 23° C. for 15 hours and precipitatesformed. The precipitates (triethylamine.HBr) were filtered out; thefiltrate was concentrated to dryness. Then the crude reaction mixturewas purified by column chromatography (SiO₂, hexane/CH₂Cl₂=5/1).N-(5-acenaphthyl)-4-tert-butylbenzylamine (1.67 g, an oil) was obtained.

Part 3: Preparation ofN-(5-Acenaphthyl)-4-tert-butylbenzylamine.mesylate

To a solution of N-(5-acenaphthyl)-4-tert-butylbenzylamine (1.1 g) indiethylether (10 mL) was added methanesulfonic acid (0.8 g) at 4° C.,then the reaction mixture was stirred at 25° C. for 10 minutes. Theresulting solution was then evaporated and dried under vacuum to affordN-(5-acenaphthyl)tert-butylbenzylamine.mesylate.

Part 4: Preparation of N-(5-Acenaphthyl)-N-(4-tert-butylbenzyl)guanidine

A mixture of N-(5-acenaphthyl)-4-tert-butylbenzylamine.mesylate (3.5mmol) and cyanamide (0.4 g) in methanol was heated at 70° C. for 40hours. During the 40 hour period, another two portions of cyanamide (0.5g, each time) were added. The reaction did not go to completion; a smallpercentage of N-(5-acenaphthyl)-4-tert-butylbenzylamine.HCl remained inthe mixture. The crude product was purified by column chromatography(SiO₂, MeOH/CH₂Cl₂=0 to 10%). The purified compound (a mixture of theguanidine and some cyanamide) dissolved in water (20 mL) was basified topH 14. Then the guanidine.free base was extracted with CH₂Cl₂ (20 mL,two times) and the combined extracts were concentrated. Finally, thepure N-(5-acenaphthyl)-N-(4-tert-butylbenzyl)guanidine was dried undervacuum for 15 hours to afford the pure product (0.6 g) as a white solid,mp: 85-86° C.; TLC:. R_(f)=0.4 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CD₃OD):δ ppm 7.60-7.20 (m, ArH, 9H), 4.90 (s, CH₂, 2H), 3.41-3.31 (m, CH₂, 4H),1.26 (s, CH₃, 9H); MS(EI): m/e 357.2 (M⁺: C₂₄H₂₇N₃.1/4H₂O); Calcd. (%):C, 79.62, H, 7.66, N, 11.60; Found (%): C, 79.47; H, 7.48, N, 11.79.

EXAMPLE 3 Preparation of N-(5-Acenaphthyl)-N′-benzhydrylguanidine.HCl

Step 1. 5-Acenaphthyl Cyanamide

5-aminoacenaphthene (7.0 g, 41.4 mmol) was dissolved in a mixture ofether (100 mL) and ethyl acetate (25 mL). To this solution was added 5.2mL of a 5 M solution of cyanogen bromide in acetonitrile (25.6 mmol ofcyanogen bromide). The solution was stirred overnight, with the gradualappearance of gray precipitate. The solid was removed by filtration (thehydrobromide of 5-aminoacenaphthene) and the resulting filtrateconcentrated in vacuo to afford a semi-solid residue. Ether (60 mL) wasadded to the residue and the mixture was stirred overnight. The solidwas removed (more hydrobromide of 5-aminoacenaphthene) and the filtrateconcentrate to approximately 20 mL and then diluted with warmcyclohexane (15 mL). Upon standing at room temperature, off-whitecrystals were deposited. They were collected, washed withcyclohexane-ether (1:1) and dried in vacuo to give 1.5 g of pureproduct, mp: 163-65° C.

Step 2. Preparation of N-(5-Acenaphthyl)-N′-benzhydrylguanidine.HCl

A mixture of 5-acenaphthyl cyanamide (0.194 g, 1 mmol) and benzhydrylamine hydrochloride (0.209 g, 0.95 mmol; prepared from benzhydryl amineand 1.0 N HCl-ether) were heated at reflux in 10 mL of chlorobenzene.After 6 hours reflux, the mixture turned into a clear solution and thereflux continued another 12 hours. The mixture was cooled to 20° C. andconcentrated on a rotavapor to give a brown syrup. This syrup wastreated with norite-A in a boiling ethanol for 20 minutes to give acolorless glass. Upon stirring this glass in anhydrous ether for 10hours at room temperature resulted in a bright white solid. The solidwas collected by filtration and washed with excess of ether and dried invacuo at 40° C. to give product (0.326 g, 79%) as a white solid, mp:225-27° C.; TLC: R_(f)=0.4 (CH₂Cl₂:MeOH; 9:1); ¹H NMR (CD₃OD): δ7.47-7.33 (m, 15H, ArH), 6.14 (s, 1H), 3.41 (bs, 4H, 2×—CH₂); MS(EI):m/e 378 (M⁺1).

EXAMPLE 4 Preparation of N,N′-bis(4-sec-Butylphenyl)guanidine.HCl

Cyanogen bromide (0.390 g, 3.7 mmol) was added in portions to a stirred4-sec-butyl aniline (0.746 g, 5 mmol) at room temperature. Ethanol(absolute) was added (4 mL) and the resultant clear reaction mixture washeated to reflux on an oil bath (bath temperature 80-85° C.) under argonfor about 30 hours. The reaction mixture was allowed to cool to roomtemperature, diluted with ethanol (15 mL), treated with Norite-A(charcoal) and then 10% NaOH solution (4-5 mL) was added (pH>10). Theresultant white solid was filtered and crystallized from ethanol-waterto give the title compound (0.204 g, 13%) as a bright white solid, mp:113-15° C.; TLC: R_(f)=0.4 (CH₂Cl₂:MeOH:NH₄OH; 9:1:2 drops); ¹H NMR(CDCl₃): δ 7.12 (d, 4H, J=8.48 Hz, ArH), 7.03 (d, 4H, J=8.45 Hz, ArH),2.56 (m, 2H, 1×—CH—), 1.57 (m, 4H, 2×—CH₂—), 1.21 (d, 6H, J=6.99 Hz,2×—CH₃), 0.82 (t, 6H, J=7.23 Hz, 2×—CH₃); MS(EI): m/e 324 (M⁺1); Anal.:C₂₁H₂₉N₃ (323.46); Calcd. (%): C, 77.97, H, 9.04, N, 12.99; Found (%):C. 77.51, H, 9.08, N, 13.16.

EXAMPLE 5 Preparation of N,N′-bis(4-sec-Butylphenyl)-N-methylguanidine.HCl

Step 1. Preparation of N-Methyl-N-4-sec-butylphenyl cyanamide

A solution of 4-sec-butylphenyl cyanamide (2.3 g, 13.56 mmol) in THF (33mL) was slowly added to a stirred suspension of sodium hydride (1.08 g,27 mmol) in THF (12 mL) at room temperature. After 2 hours reflux, thereaction mixture was cooled to 20° C., methyl iodide (7.04 g, 49.6 mmol)was added and the mixture stirred the contents at 20° C. After 19 hours,the reaction was quenched by careful addition of methanol (45 mL)followed by water (100 mL). The aqueous mixture was extracted withmethylene chloride (3×90 mL), dried over MgSO₄ and the residue waspurified on flash chromatography to yield the product (2.0 g, 79%) as aorange syrup. TLC (CHCl₃:CH₃OH; 10:1); R_(f)=0.76.

Step 2. Preparation of N,N′-bis(4-sec-Butylphenyl)-N-methylguanidine.HCl

Aluminum chloride (0.42 g, 3.1 mmol) was added to a stirred solution ofN-4-sec-butylphenyl-N-methyl cyanamide (0.534 g, 2.84 mmol) inchlorobenzene (15 mL) at 145° C. After 10 minutes 4-sec-butylphenylamine hydrochloride (0.474 g, 2.56 mmol, prepared from 4-sec-butylaniline and 1.0 M HCl-ether) was added and continued reflux. After 2hours, the reaction mixture was evaporated and the product was purifiedby flash chromatography to afford the title compound (0.45 g, 65%) as asyrup. TLC: R_(f)=0.22 (CH₂Cl₂:CH₃OH; 10:1); ¹H NMR (CD₃OD): δ 7.27 (d,4H, J=8.18 Hz, ArH), 7.20 (d, 4H, J=8.36 Hz, ArH), 3.46 (s, 3H, —NCH₃),2.69-2.58 (m, 2H, 2×—CH), 1.68-1.57 (m, 4H 2×—CH₂), 1.25 (d, 6H,2×—CH₃), 0.85 (t, 6H, 2×—CH₃); HRMS: 337.2484 (337.2528 Calcd. forC₂₂H₃₁N₃); HPLC: (CH₃CN:H₂O; 50:50 with 0.1% TFA): 98% pure.

EXAMPLE 6 Preparation ofN,N′-Bis(4-sec-butylphenyl-N,N′-bis-methylguanidine.HCl

Step 1. Preparation of N-Methyl-N-4-sec-butylphenyl cyanamide Preparedas per Step 1 of Example 5 above.

Step 2. Preparation of N-Methyl-N-4-sec-butyl aniline

4-sec-butyl aniline (4.28 g, 28.7 mmol) was dissolved in formic acid(97%, 1.85 g, 40.2 mmol) and magnetically stirred at 100-105° C. underargon. After 6 hours, the reaction mixture was cooled to 25° C. anddiluted with dichloromethane (40 mL). The mixture was washed withsaturated sodium bicarbonate (3×30 mL), brine (3×30 mL) and the organicphase dried over MgSO₄ and then evaporated to afford the formamide (3.85g, 76%) as an amber syrup, which was used in the next step withoutfurther purification.

LiAlH₄-THF solution (1.0 M, 1.0 g, 26 mmol) in THF (23 mL) at ice-bathtemperature. After stirring the contents at 25° C. for 20 hours, thereaction mixture was combined with saturated solution of sodium sulfate(150 mL) then filtered and washed with THF. The filtrate was evaporatedand the residue was chromatographed on silica gel using hexane/ethylacetate (8:2) as eluent to afford the title compound (1.76 g, 50%) as aliquid.

Step 3. Preparation of N,N′-Bis(4-sec-butylphenyl)-N,N′-bis-methylguanidine.HCl

Aluminum chloride (0.39 g, 2.93 mmol) was added to a stirred solution of4-sec-butylphenyl-N-methyl cyanamide (0.5 g, 2.66 mmol) in chlorobenzene(14 mL) at 145° C. After 10 minutes 4-sec-butylphenyl-N-methyl aminehydrochloride (0.466 g, 2.34 mmol; prepared from4-sec-butylphenyl-N-methyl amine and 1.0 M HCl-ether) was added andcontinued reflux. After 5 hours, the reaction mixture was evaporated onrotavapor and the product was purified by flash chromatography usingchloroform/methanol (10:1) to afford the title compound (0.34 g, 38%) asan extremely hygroscopic solid, mp: 65-66IC; TLC: R_(f)=0.13(CHCl₃:CH₃OH; 10:1); ¹H NMR (CD₃OD): δ 6.99 (d, 4H, J=8.46 Hz, ArH),6.80 (d, 4H, J=8.34 Hz, ArH), 3.36 (s, 6H, 2×—NCH₃), 2.50 (m, 2H,2×—CH), 1.58-1.53 (m, 4H, 2×—CH₂), 1.16 (d, 6H, 2×—CH₃), 0.79 (t, 6H,J=7.35 Hz, 2×—CH₃); HRMS: 351.2660 (351.2674 Calcd. for C₂₃HH₃₃N₃);Anal.: C₂₃H₃₃N₃HCl; 1.75 H₂O (418.74); Calcd. (%): C, 66.19, H, 8.64, N,10.07; Found (%): C, 66.56, H, 8.55, N, 11.27; HPLC: (CH₃CN:H₂O 50:50with 0.1% TFA): 99% pure.

EXAMPLE 7 Preparation ofN-(5-Acenaphthyl)-N′-(1,2,3,4-tetrahydroquinolinyl)guanidine.mesylate

Part 1: Preparation of 5-Acenaphthyl cyanamide

A mixture of 5 and 3-nitroacenaphthene was reduced with Pd/C in ethylacetate under hydrogen at 40 psi pressure and the resulting amines wereseparated by recrystallization from cyclohexane/ethyl acetate.5-acenaphthyl amine further reacted with cyanogen bromide to yield5-acenaphthyl cyanamide.

Part 2: Preparation ofN-(5-Acenaphthyl)-N′-(1,2,3,4-tetrahydroguinolinyl) guanidine.mesylate

A mixture of 5-acenaphthyl cyanamide (582 mg, 3 mmol),1,2,3,4-tetrahydroquinolinyl.mesylate (688 mg, 3 mmol), andchlorobenzene (2 mL) in a round bottom flask were heated at 150-160° C.for 1 hour and a precipitate formed. The precipitate was collected byfiltration, washed with ether, and dried under vacuum to yield the pureproduct (1.25 g) as a white solid, mp: 203-204° C.; TLC: R_(f)=0.3(SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CD₃OD): δ ppm 7.70-7.15 (m, ArH, 9H),3.90 (t, CH₂, 2H), 3.44-3.35 (m, CH₂, 4H), 2.87 (t, CH₂, 2H), 2.69 (s,CH₃, 3H), 2.15 (m, CH₂, 2H); MS(EI): m/e 327.2 (M⁺: C₂₂H₂₁N₃); Anal.:(C₂₃H₂₅N₃O₃S); Calcd. (%): C, 65.23, H, 5.95, N, 9.92; Found (%): C,64.81, H, 6.00, N, 9.74.

EXAMPLE 8 Preparation ofN,N′-Bis-(4-sec-butylphenyl)-2-iminopyrimidazolidine.HBr

Part 1: Preparation of N,N′-Bis-(4-sec-butylphenyl)melonyldiamide

Malonyldichloride (10 mmol) in methylene chloride (19 mL) was addeddropwise to a solution of 4-sec-butylaniline (52 mmol) in methylenechloride (30 mL) over a period of 10 minutes at 4° C. After the exothermsubsided, the solution was removed from ice bath and stirred at 25° C.for 2 hours. The methylene chloride solution was concentrated down todryness. The crude reaction mixture was purified by columnchromatography (SiO₂, CH₂Cl₂/EtOAc=2/1) to yield the pureN,N′-bis-(4-sec-butylphenyl)melonyldiamide (75% in yield).

Part 2: Preparation of N,N′-Bis-(4-sec-butylphenyl-1,3-diaminopropane

Diborane (38.24 mmol, 38.24 mL, 1M) in THF was added dropwise to a dryTHF solution of N,N′-bis-(4-sec-butylphenyl)melonyldiamide (9.56 mmol)over 10 minutes at 4° C. After 15 minutes, the reaction mixture washeated at refluxing temperature for 16 hours. The reaction mixture wasthen quenched by aqueous HCl (1M) at 0° C. Then the THF was evaporated,and the solution was basified to pH 14 and extracted with CH₂Cl₂. Thecombined organic extracts were dried over MgSO₄, filtered, andconcentrated to yield the pureN,N′-bis-(4-sec-butylphenyl)-1,3-diaminopropane as a yellow liquid (78%in yield).

Part 3: Preparation ofN,N′-Bis-(4-sec-butylphenyl-2-imino-pyrimidazolidine.HBr

N,N′-bis-(4-sec-butylphenyl)-1,3-diaminopropane (1.69 g, 5 mmol) in EtOH(15 mL) was added cyanogen bromide, then the solution was brought toreflux for 16 hours. After the reaction, the mixture was concentrateddown and purified by column chromatography (SiO₂, MeOH/CH₂Cl₂=0% to10%). The pure N,N′-bis-(4-sec-butylphenyl)-2-imino-pyrimidazolidine.HBrwas obtained as a white solid (75% in yield), mp: >250° C.; TLC:R_(f)=0.5 (SiO₂, CH₂Cl₂/MeOH=9/1); MS(EI): m/e 363.2 (M⁺: C₂₄H₃₃N₃);Anal.: (C₂₄H₃₃N₃.HBr.1/4H₂O); Calcd: (%): C, 64.17, H, 7.74, N, 9.40;Found 1%): C, 64.18, H, 7.82, N, 9.19.

EXAMPLE 9 Preparation of N-N′-Bis(3-fluoroanthenyl)guanidinehydrobromide

To a solution of 3-aminofluoroanthene (1.95 g, 8.98 mmol) in ethanol(100.0 ml) was slowly added cyanogen bromide 10.922 g, 8.7 mmol) whilethe flask was surrounded by an ice bath and under static Ar. Thesolution was refluxed for 9.5 hours then let stir at room temperaturefor 18 hours. The yellow mixture was suction filtered and the yellowsolid washed with ether and a little ethyl acetate to yield the titlecompound as a yellow solid, 1.53 g, 63.0% yield.

Yellow solid; mp: >300° C.; R_(f)=0.24 (10:1 CHCl₃/MeOH); ¹H NMR (300MHz, CD₃OD) d 8.10-8.55 (m, 6H, Ar—H), 7.94-8.00 (m, 4H, ArH), 7.73-7.85(m, 4H, ArH), 7.39-7.42 (m, 4H, ArH); MS(EI): m/e 459 (M⁺ for freebase); Anal. Calcd. for C₃₃H₂₁N₃.HBr: C, 73.34, H, 4.1, N, 7.77; Found:C, 73.34, H, 4.48, N, 6.94, 6.76.

EXAMPLES 10-145

By methods indicated above and using appropriately substituted reagents,the following compounds were prepared having the specified physicalcharacteristics.

EXAMPLE 10N-(5-Acenaphthyl)-N′-[(1-naphthyl)-methylene]guanidine.CH₃SO₃H

White solid; mp: 262° C.

EXAMPLE 11 N-(2-Naphthyl)-N′-(4-isopropylphenyl)guanidine.HCl

White solid; mp: 208-10° C.; ¹H NMR (CDCl₃): δ 7.82-7.15 (m, 11H, ArH),2.90-2.75 (m, 1H, —CH), 1.16 (d, 6H, J=6.84 Hz, 2×—CH₃); HRMS: 303.1738(303.1735 Calcd. for C₂₀H₂₁N₃).

EXAMPLE 12 N,N′-Bis(2-fluorenyl)guanidine.HBr

White solid; mp: 281° C.

EXAMPLE 13 N,N′-Bis(4-tort-butylphenyl)guanidine

White solid; mp: 161-62° C.; TLC (CHCl₃:CH₃OH; 9:1): R_(f)=0.54; ¹H NMR(CDCl₃): δ 7.34 (d, 4H, J=8.57 Hz, ArH), 7.05 (d, 4H, J=8.52 Hz, ArH),1.28 (s, 18H, 2×—CH₃); HRMS: 323.2372 (323.2362 Calcd. for C₂₁H₂₉N₃).

EXAMPLE 14N-(4-tert-Butylphenyl)-N′-(2,3,4-trichlorophenyl)guanidine.HCl

White solid; mp: 227-29° C.; TLC (CH₂Cl₂:CH₃OH; 9:1): R_(f)=0.43; ¹H NMR(CD₃OD): δ 7.63 (d, 1H, J=8.7 Hz, ArH), 7.52 (d, 2H, J=8.67 Hz, ArH),7.44 (d, 1H, J=8.67 Hz, ArH), 7.27 (d, 2H, J=8.66 Hz, ArH), 1.33 (s, 9H,3×—CH₃); Anal. Calcd. for C₁₇H₁₈N₃Cl.HCl (414.17): C, 50.15; H, 4.7; N,10.32. Found: C, 49.97; H, 4.57; N, 10.22.

EXAMPLE 15N-(4-Methoxy-1-naphthyl)-N′-(2,3,4-trichlorophenyl)guanidine.HCl

White solid; mp: 238-40° C.; TLC (CH₂Cl₂:CH₃OH; 9:1): R_(f)=0.48; ¹H NMR(CD₃OD): δ 8.45 (d, 1H, J=8.43 Hz, ArH), 8.08 (d, 1H, J=8.24 Hz, ArH),7.82-7.63 (m, 5H, ArH), 7.13 (d, 1H, J=8.27 Hz, ArH), 4.19 (s, 3H,—OCH₃); Anal. Calcd. for C₁₈H₁₄N₃Cl₃.HCl (431.14): C, 50.14; H, 3.51; N,9.75.; Found: C, 49.38; H, 3.59; N, 9.57.

EXAMPLE 16 N-(2-Naphthyl)-N′-(2-adamantyl)guanidine.HCl

White solid; mp: 219-20° C.; ¹H NMR (CDCl₃): δ 7.81-7.22 (m, 7H, ArH),1.97-1.51 (m, 15H, ArH); Anal. Calcd. for ₂₁H₂₅N₃.HCl (355.45): C,70.90; H, 7.31; N, 11.82; Found: C, 70.90, H, 7.34; H, 11.73.

EXAMPLE 17 N-(4-sec-Butylphenyl)-N-benzylguanidine

mp: 65-67° C.; TLC: R_(f)=0.5 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CD₃OD): δ7.30-6.90 (m, ArH, 9H), 4.98 (s, CH₂, 2H), 2.58 (m, CH, 1H, 1.55 (m,CH₂, 2H), 1.20 (d, CH₃, 3H), 0.79 (t, CH₃, 3H); HRMS: 281.1891 (281.1891calculated for C₁₈H₂₃N₃).

EXAMPLE 18 N-(5-Acenaphthyl)-N-benzylguanidine

mp: 138-140° C.; TLC: R_(f)=0.5 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CD₃OD):δ 7.45-6.93 (m, ArH, 10H), 5.54 (d, CH₂, J=15.8 Hz, 1H), 4.63 (d, CH₂,J=15.6 Hz, 1H), 3.45-3.40 (m, CH₂, 4H); HRMS: 301.1559 (301.1589calculated for C₂₀H₁₉N₃).

EXAMPLE 19 N-(5-Acenaphthyl)-N-(4-isopropylbenzyl)guanidine

mp: 153-155° C.; TLC: R_(f)=0.3 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CD₃OD):δ ppm 7.60-7.10 (m, ArH, 9H), 5.17 (d, CH₂, J=16.2 Hz, 1H), 4.57 (d,CH₂, J=16.1 Hz, 1H), 3.45-3.40 (m, CH₂, 4H), 2.85 (m, CH, 1H), 1.20 (d,CH₃, 6H); HRMS: 343.2048 (343.2067 calculated for C₂₃H₂₅N₃); HPLC: 92%pure.

EXAMPLE 20 N-(4-Cyclohexylphenyl)-N-(4-isopropylbenzyl)guanidine.HCl

mp: 130-131° C.; TLC: R_(f)=0.4 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR CCD₃OD):δ ppm 7.35-7.12 (m, ArH, 8H), 4.92 (s, CH₂, 2H), 2.90 (m, CH, 1H), 2.53(m, CH, 1H), 1.87-1.25 (m, CH₂, 10H), 1.12 (d, CH₃, 6H); HRMS: 349.2512(349.2518 calculated for C₂₃H₃₁N₃); HPLC: 99% pure.

EXAMPLE 21 N-(4-Cyclohexylphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

mp: 219-220° C.; TLC: R_(f)=0.4 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CDCl₃):δ ppm 7.45-7.18 (m, ArH, 8H), 4.88 (s, CH₂, 2H), 2.55 (s, CH, 1H),1.90-1.30 (m, CH₂, 10H), 1.32 (s, CH₃, 9H); MS(EI): m/e 363.2 (M⁺:C₂₄H₃₃N₃); Anal.: (C₂₄H₃₃N₃.HCl); Calcd. (%): C, 72.06, H, 8.57, N,10.50; Found (%): C, 71.97, H, 8.32, N, 10.33.

EXAMPLE 22 N-(2-Fluorenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

mp: 155-157° C.; TLC: R_(f)=0.6 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CDCl₃):δ 7.90-7.20 (m, ArH, 11H), 4.95 (s, CH₂, 2H), 3.95 (s, CH_(2, 2)H), 1.32(s, CH₃, 9H); MS(EI): m/e 369.2 (M⁺: C₂₅H₂₇N₃); Anal.:(C₂₅H₂₇N₃.HCl.H₂O); Calcd. (%): C, 70.89, H, 7.14, N, 9.93; Found (%):C, 71.14, H, 6.88, N, 9.77.

EXAMPLE 23 N-(4-sec-Butylphenyl)-N-(trans-cinnamyl)guanidine.HCl

mp: 169-170° C.; TLC: R_(f)=0.2 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CDCl₃):δ ppm 7.40-7.20 (m, ArH, 9H), 6.68 (d, CH, J=16 Hz, 1H), 6.25 (dt, CH,J=16 Hz, 1H), 4.55 (d, CH₂, 2H), 2.66 (m, CH, 1H), 1.60 (m, CH₂, 2H),1.25 (d, CH₃, 3H), 0.83 (t, CH₃, 3H); Anal.: (C₂₀H₂₅N₃.HCl); Calcd. (%):C, 69.93, H, 7.64, N, 12.24; Found (%): C, 69.79, H, 7.45, N, 12.29.

EXAMPLE 24 N-(4-n-Butoxyphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

mp: 188-189° C.; TLC: R_(f)=0.5 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CDCl₃):δ ppm 7.446.90 (m, ArH, 8H), 4.84 (s, CH₂, 2H), 3.97 (t, CH₂, 2H), 1.73(p, CH₂, 2H), 1.49 (p, CH₂, 2H), 1.32 (s, CH₃, 9H), 0.94 (t, CH₃, 3H);MS(El): m/e 353.3 (M⁺: C₂₂H₃₁N₃O); Anal.: (C₂₂H₃₁N₃O.HCl); Calcd. (%):C, 67.83, H, 8.29, N, 10.79; Found (%): C, 68.00, H, 8.18, N, 11.04.

EXAMPLE 25 N-(3-Biphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

mp: 255-256° C.; TLC: R_(f)=0.5 (SiO, CH₂Cl₂/MeOH=9/1); ¹H NMR (CDCl₃):δ 7.70-7.15 (m, ArH, 13H), 4.93 (s, CH₂, 2H), 1.30 (s, CH₃, 9H); MS(EI):m/e 357.3 (M⁺: C₂₄H₂₇N₃); Anal.: (C₂₄H₂₇N₃.HCl); Calcd. (%): C, 73.25,H, 7.18, N, 10.68; Found (%): C, 73.41, H, 7.18, N, 10.86.

EXAMPLE 26 N-(5-Indanyl)-N-(4-tert-butylbenzyl)guanidine.HCl

TLC: R_(f)=0.5 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CDCl₃): δ ppm 7.45-6.90(m, ArH, 7H), 4.86 (s, CH₂, 2H), 2.87 (m, CH₂, 4H), 2.08 (m, CH₂, 2H),1.29 (s, CH₃, 9H); MS(EI): m/e 321.2 (M⁺: C₂₁H₂₇N₃).

EXAMPLE 27N-(3-Trifluoromethoxyphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

TLC: R_(f)=0.5 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CDCl₃): δ ppm 7.65-7.10(m, ArH, 8H), 4.94 (s, CH₂, 2H), 1.29 (s, CH₃, 9H); MS(EI): m/e 365.1(M⁺: C₁₉H₂₂F₃N₃O).

EXAMPLE 28 N-(Methoxy-1-naphthyl)-N-(4-tert-butylbenzyl)guanidine.HCl

TLC: R_(f)=0.5 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CDCl₃: δ ppm 8.35-6.80(m, ArH, 10H), 5.25 (d, CH₂, J=15.6 Hz, 1H), 4.59 (d, CH₂, J=15.6 Hz,1H), 1.29 (s, CH₃, 9H); MS(El): m/e 361.5 (M⁺: C₂₃H₂₇N₃O).

EXAMPLE 29 N-(5-Acenaphthyl)-N′-(indolinyl)guanidine.mesylate

mp: 249-250° C.; TLC: R_(f)=0.3 (SiO₂, CH₂Cl₂/MeOH=9/1); ¹H NMR (CD₃OD):δ ppm 7.70-7.15 (m, ArH, 9H), 4.27 (t, CH₂, 2H), 3.44-3.35 (m, CH₂, 4H),3.30 (t, CH₂, 2H), 2.69 (s, CH₃, 3H); MS(EI): m/e 313.2 (M⁺: C₂₁H₁₉N₃);Anal.: (C₂₂H₂₃N₃O₃S.1/2H₂O); Calcd. (%): C, 63.13, H, 5.78, N, 10.04;Found (%): C, 63.13, H, 5.70, N, 10.06.

EXAMPLE 30 N,N′-Bis(3-biphenyl)guanidine.HBr

White solid; mp: 176-178° C.; TLC(CH₂Cl₂:CH₃OH; 15:1): R_(f)=0.50; ¹HNMR (CD₃OD): 7.66-7.33 (m, ArH). Anal. Calcd. for C₂₅H₃₃N₃.HBr (444.37):C, 67.27; H, 5.42; N, 9.41.; Found: C, 67.01, H, 4.86, N, 9.29.

EXAMPLE 31 N,N′-Di-(3-tert-butylphenyl)guanidine.HBr

White solid; mp: 206-208° C.; TLC (CH₂CL₂: MeOH; 15:1): R_(f)=0.50; ¹HNMR (CD₃OD): 7.53-7.23 (m, 8H, ArH), 1.34 (s, 18H, —C(CH₃)₃); Anal.Calcd. for C₂₁H₂₉N₃₂.HBr (404.39): C, 62.37, H,7.48, N, 10.39; Found: C,62.49, H, 7.45, N, 10.52.

EXAMPLE 32 N,N′-Bis-(4-methoxy-1-naphthyl)guanidine.HBr

Light green solid; mp: 236-238° C.; TLC (CH₂CL₂:MeOH; 15:1): R_(f)=0.48;¹H NMR (CD₃OD): 8.32 (d, 2H, J=7.72 Hz, ArH), 7.97 (d. 2H, J=8.18 Hz,ArH), 7.69 (t, 2H, J=7.52 Hz, ArH), 7.57 (q, 4H, J=7.52 Hz, ArH), 7.00(d, 2H, J=8.18 Hz, ArH), 4.05 (s, 3H, —OCH₃); Anal. Calcd. forC₂₃H₂₁N₃O₂.HBr (452.35): C, 61.07, H, 4.90, N, 9.29; Found: C, 60.98, H,4.99, N, 9.50.

EXAMPLE 33 N,N′-Bis-(5-indanyl)guanidine.HBr

White solid; mp: 118-120° C.; TLC (CH₂Cl₂:MeOH; 15:1): R_(f)=0.31; ¹HNMR (CD₃OD): 7.30 (d, J=8.25 Hz, 2H, ArH), 7.18 (s, 2H, ArH), 7.07 (d,2H, J=7.27 Hz, ArH), 2.93 (q, J=7.10 Hz, 8H, —CH₂), 2.11 (p, 4H, —CH₂,J=7.42 Hz); Anal. Calcd. for C₁₉H₂₁N₃.HBr (372.31): C, 61.30, H, 5.96,N, 11.29; Found: C, 61.12; H, 5.81; N, 11.11.

EXAMPLE 34 N,N′-Bis-(3-sec-butylphenyl)guanidine.HBr

White solid; mp: 85-87° C.; TLC(CH₂Cl₂:MeOH; 15:1): R_(f)=0.31; ¹H NMR(CD₃OD): 7.39 (t, J=7.57 Hz, 2H, ArH), 7.17 (t, J=7.15 Hz, 4H, ArH),2.65 (m, 2H, —CH), 1.64 (m, 4H, —CH₂), 1.58 (d, J=0.82 Hz, 6H, —CH₃),0.84 (t, J=1.90 Hz, 6H, —CH₃); Anal. Calcd. for C₂₁H₂₉N₃.HBr (404.39):C, 62.37, H, 7.29, N, 10.39; Found: C, 62.58, H, 7.29, N, 10.61.

EXAMPLE 35 N,N′-Bis(4-tert-butylphenyl)-N-methylguanidine.HBr

White solid; mp: 194-196° C.; TLC (CH₂Cl₂: MeOH; 10:1): R_(f)=0.35; ¹HNMR (CD₃OD): 7.60-7.57 (d. J=8.39 Hz, 2H, ArH), 7.51-7.48 (d, J=8.24 Hz,2H, ArH), 7.38-7.35 (d, J=8.52 Hz, 2H, ArH), 7.22-7.20 (d, J=8.24 Hz,2H, ArH), 3.46 (s, 1H, —CH₃), 1.35 (s, 9H, —C(CH₃)₃), 1.33 (s, 9H,—C(CH₃)₃); Anal. Calcd. for C₂₂H₃₁N₃.HCl(373.97): C, 70.66, H, 8.62, N,11.29; Found: C, 70.69, H, 8.31, N, 11.39.

EXAMPLE 36 N,N′-Bis(4-tert-butylphenyl)-N,N′-methylguanidine.HBr

White solid; mp: 175-177° C.; TLC(CH₂Cl₂:MEOH; 10:1): R_(f)=0.39; ¹H NMR(CD₃OD): 7.21-7.18 (d, J=8.52 Hz, 4H, ArH), 6.80-6.78 (d, J=8.51 Hz, 4H,ArH), 3.35 (s, 6H, —CH₃), 1.26 (s, 18H, —C(CH₃)₃); Anal. Calcd. forC₂₃H₃₃N₃.HCl(388.00): C, 71.20, H, 8.83, N, 10.83; Found: C, 70.88, H,8.61, N, 10.75.

EXAMPLE 37 N,N′-Bis(4-n-butylphenyl)guanidine.mesylate

White solid: M.P. 120-22° C.; ¹H NMR (300 MHz, CD₃OD): δ 7.28 (dd, 4H,J=8.5 Hz and J=2.2 Hz, ArH); 7.23 (dd, 4H, J=8.5 Hz and J=2.2 Hz, ArH);2.69 (s, 3H, —SO₃H—CH₃); 2.64 (t, 4H, J=7.69 Hz, 2×ArCH₂—); 1.65-1.55(m, 4H, 2×—CH₂—CH₂CH₃); 1.43-1.30 (m, 4H, 2×—CH₂—CH₃); 0.94 (t, 6H,J=7.35 Hz, 2×—CH₃); Anal Calcd. for C₂₁H₂₉N₃.CH₄SO₃ (419.56): C, 62.98,H, 7.93, N, 10.01; Found: C, 62.96, H, 7.69, N, 9.93.

EXAMPLE 38 N-(5-Acenaphthyl)-N′-(1-methyl-2-phenoxyethyl)guanidine.HCl((5-C₁₂H₉)NHC(═NH)NHCH(CH₃)CHOC₆H₅.HCl)

Bubbly white solid: mp: 107-110° C.; R_(f)=0.24 (10:1 CHCl₃/MeOH); ¹HNMR (300 MHz, CD₃OD): δ 7.29-7.56 (m, 7H, ArH), 6.96-7.01 (t, 3H, J=16Hz, ArH), 4.20-4.32 (m, 1H, CH), 4.11-4.89 (m, 1H, CH), 3.90-4.00 (m,1H, CH), 3.40-3.50 (m, 4H, CH₂); MS(EI): m/e 345 (M⁺ for free base);Anal. Calcd. for C₂₂H₂₃N₃O.HCl: C, 69.19, H, 6.33, N, 11.00; Found: C,69.07, H, 6.40, N, 10.87.

EXAMPLE 39 N-(5-Acenaphthyl)-N′-(piperonyl)guanidine.HCl

Tan solid: mp: 142-144° C.; R_(f)=0.20 (10:1 CHCl₃/MeOH); ¹H NMR (300MHz, CD₃OD): δ 7.34-7.54 (m, 5H, ArH), 6.84 (s, 3H, ArH), 5.98 (s, 2H,CH₂), 4.41 (s, 2H, CH₂), 3.43-3.50 (m, 4H, 2-CH₂); MS(EI): m/e 345 M⁺for free base); Anal. Calcd. for C₂₁H₁₉N₃O₂.HCl.0.5C₄H₈O₂: C, 64.92, H,5.69, N, 9.88; Found: C, 64.37, H, 5.93, N, 10.25.

EXAMPLE 40N-(5-Acenaphthyl)-N′-(1-methyl-2-(4-chlorophenyl)ethyl)guanidine.HCl((5-C₁₂H₉)NHC(═NH)NHCH(CH₃)CH(4-ClC₆H₄.HCl)

Bubbly amber solid: M.P. 123-125° C.; R_(f)=0.22 (10:1 CHCl₃/MeOH); ¹HNMR (300 MHz, CD₃OD): δ 7.51-7.54 (m, 1H, ArH), 7.18-7.37 (m, 8H, ArH),4.00-4.12 (m, 1H, CH), 3.41-3.51 (m, 4H, 2-CH₂), 2.90-3.00 (dd, 1H, CH),2.71-2.82 (dd, 1H, CH) 1.33-1.35 (d, 3H, J=6.53 Hz, CH₃); MS(EI): m/e363 (M⁺ for free base); Anal. Calcd. for C₂₂H₂₂N₃Cl.HCl: C, 66.00, H,5.79, N, 10.50; Found: C, 65.94, H, 5.91, N, 10.30.

EXAMPLE 41 N-(5-Acenaphthyl)-N′-(1,2-diphenylethyl)guanidine.HCl

Cream colored solid: M.P. 167-170° C.; R_(f)=0.18 (10:1 CHCl₃/MeOH); ¹HNMR (300 MHz, CD₃OD): δ 7.16-7.44 (m, 15H, ArH), 5.1-5.2 (m, 1H, CH)3.30-3.41 (m, 4H, 2-CH₂), 3.13-3.30 (m, 2H, CH₂); MS(EI): m/e 391 (M⁺for free base); Anal. Calcd. for ₂₇H₂₅N₃.HCl: C, 75.77, H, 6.12, N,9.82; Found: C, 75.60, H, 6.00, N, 9.71.

EXAMPLE 42 N-(3-Benzyloxyphenyl)-N′-(4-benzyloxyphenyl)guanidine.HCl

Bubbly pink solid: mp: 59-62° C.; R_(f)=0.19 (10:1 CHCl₃/MeOH); ¹H NMR(300 MHz, CD₃OD): δ 7.24-7.45 (m, 13H, ArH), 6.90-7.10 (m, 5H, ArH),5.12 (brs, 4H, 2-CH₂); MS(EI): m/e 423 (M⁺ for free base); Anal. Calcd.for C₂₇H₂₅N₃O₂.HCl.1.5H₂O: C, 66.64, H, 6.01, N, 8.64; Found: C, 67.21,66.95, H, 6.12, 6.01, N, 8.25, 7.98.

EXAMPLE 43 N-(5-Acenaphthyl)-N′-(3-phenylpropyl)guanidine.HCl

White solid: mp: 84° C.; R_(f)=0.28 (1:5 MeOH:EtOAc); ¹H NMR (300 MHz,CD₃OD): δ 7.54-7.57 (m, 2H, ArH), 7.35-7.41 (m, 3H, ArH), 7.25-7.35 (m,2H, ArH), 7.18-7.24 (m, 3H, ArH), 3.40-3.48 (brs, 4H, 2-CH₂), 3.29-3.34(t, J=7 Hz, 2H, CH₂—N), 2.66-2.71 (t, J=8 Hz, 2H, CH₂), 1.91-2.00 (m,2H, CH₂—Ar); MS(EI): m/e 329 (M⁺ for free base); Anal. Calcd. forC₂₄H₂₁N₃.HCl.0.5H₂O: C, 70.48, H, 6.72, N, 11.26; Found: C, 70.52. H,6.65, N, 11.18.

EXAMPLE 44 N-(5-Acenaphthyl)-N′-(2-methyl-2-phenylethyl)guanidine.HCl

White solid: mp: 110° C.; R_(f)=0.26 (1:5 MeOH:EtOAc); ¹H NMR (300 MHz,CD₃OD): δ 7.49-7.54 (t, J=7 Hz, 1H, ArH), 7.24-7.38 (m, 8H, ArH),7.15-7.18 (m, 1H, ArH), 3.51-3.53 (d, J=6 Hz, 2H, CH₂—Ar), 3.38-3.48 (m,4H, 2-CH₂), 3.03-3.10 (m, 1H, CH), 1.30-1.33 (d, J=7 Hz, 3H, CH₃);MS(EI): m/e 329 (M⁺ for free base); Anal. Calcd. forC₂₄H₂₁N₃.HCl.0.5H₂O: C, 70.48, H, 6.72, N, 11.26; Found: C, 70.62, H,6.58, N, 11.17.

EXAMPLE 45 N,N′-(sec-Butylphenyl)-N′-(2-phenoxyethyl)guanidine.HCl

Semisolid: R_(f)=0.20 (1:5 MeOH:EtOAc); ¹H NMR (300 MHz, CD₃OD): δ7.22-7.34 (m, 6, ArH). 7.16-7.22 (d, J=7 Hz, 2, ArH), 7.00-7.07 (d, J=7Hz, 2H, ArH), 6.87-6.98 (m, 3H, ArH), 4.20 (brs, 4H, 2-CH₂), 2.51-2.70(m, 2H, 2-CH), 1.53-1.68 (m, 4H, 2-CH₂), 1.20-1.27 (2d, J=6 Hz, 6H,2-CH₃); MS(EI): m/e 444 (M⁺ for free base); Anal. Calcd. forC₂₉H₃₇N₃O.0.75HCl: C, 73.96, H, 8.08, N, 8.92; Found: C, 74.21, H, 8.26,N, 9.21.

EXAMPLE 46 N,N′-(sec-Butylphenyl)-N′-(n-pentyl)guanidine.HCl

White solid: R_(f)=0.17 (1:5 MeOH:EtOAc); ¹H NMR (300 MHz, CD₃OD):67.31-7.38 (m, 4H, ArH), 7.25-7.28 (d, J=8.5 Hz, 2H, ArH), 7.16-7.19 (d,J=8.5 Hz, 2H, ArH), 3.75-3.80 (t, J=8 Hz, 2H, N—CH₂), 2.59-2.71 (m, 2H,2-CH), 1.56-1.68 (m, 6H, 3-CH₂), 1.30-1.34 (m, 4H, 2-CH₂), 1.22-1.26(2d, J=7 Hz, 6H, 2-CH₃), 0.80-0.91 (m, 9H, 3-CH₃); MS(EI): m/e 394 (M⁺for free base); Anal. Calcd. for C₂₆H₃₉N₃.HCl.H₂O: C, 69.69, H, 9.45, N,9.38; Found: C, 69.89, H, 8.88, N, 10.09.

EXAMPLE 47 N-(1-Naphthyl)-N-4(tert-butylbenzyl)guanidine.HCl

¹H NMR (CDCl₃): δ ppm 8.35-7.10 (m, ArH, 11H), 5.25 (d, CH₂, J=15.6 Hz,1H), 4.67 (d, CH₂, J=15.6 Hz, 1H), 1.29 (s, CH₃, 9H). MS(El): m/e 331(M⁺: C₂₂H₂₅N₃); Anal. (C₂₂H₂₅N₃.HCl): Calcd. (%): C, 71.82, H, 7.12, N,11.42; Found (%): C, 71.79, H, 7.12, N, 11.43; TLC: R_(f)=0.50 (SiO₂,CH₂Cl₂/MeOH=9/1); mp: 241-242° C.

EXAMPLE 48 N-(3-Iodophenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.78-7.13 (m, ArH, 8H), 4.87 (s, ArCH₂, 2H), 1.30(s, CH₃, 9H); MS(EI): m/e 407.3 (M⁺: C₁₈H₂₂N₃l); Anal. (C₁₈H₂₂lN₃.HCl):cal.(%): C, 48.72, H, 5.22, N, 9.47; found (%): C, 48.90, H, 5.46, N,9.52; TLC: R_(f)=0.42 (SiO₂, CH₂Cl₂/MeOH=10/1); mp: 271-272° C.

EXAMPLE 49 N-(4-Chloro-1-naphthyl)-N-(4-tert-benzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 8.37-7.13 (m, ArH, 10H), 5.25 (d, CH₂, J=15.5 Hz,1H), 4.69 (d, CH₂, J=15.4 Hz, 1H), 1.26 (s, CH₃, 9H); MS(El): m/e 365.1(M⁺: C₂₂H₂₄ClN₃); Calcd. (C₂₂H₂₄ClN₃.HCl.H₂O): Calcd. (%): C, 62.86, H,6.47, N, 10.03; Found (%): C, 63.19, H, 6.27, N, 9.69; TLC: R_(f)=0.52(SiO₂, CH₂Cl₂/MeOH=10/1); mp: 115-117° C.

EXAMPLE 50 N-(4-tert-Butylphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

¹H NMR (CDCl₃): δ ppm 7.51-7.18 (m, ArH, 8H), 4.93 (s, ArCH₂, 2H), 1.33(s, CH₃, 9H), 1.31 (s, CH₃, 9H); MS(El): m/e 338 (M⁺: C₂₂H₃₁N₃); Anal.(C₂₂H₃₁N₃.HCl): Calcd. (%): C, 70.66, H, 8.62, N, 11.24; Found (%): C,70.43, H, 8.42, N, 11.17; TLC: R_(f)=0.45 (SiO₂, CH₂Cl₂/MeOH=10/1); mp:290-291° C.

EXAMPLE 51 N-(4-Iodophenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.81-7.02 (m, ArH, 8H), 4.89 (s, ArCH₂, 2H), 1.30(s, CH₃, 9H); MS(EI): m/e 408 (M⁺: C₁₈H₂₂N₃l); Anal. (C₁₈H₂₂lN₃.HCl):Calcd. (%): C, 48.72, H, 5.22, N, 9.47; Found (%): C, 48.72, H, 5.26, N,9.28; TLC: R_(f)=0.45 (SiO₂, CH₂Cl₂/MeOH=10/1); mp: 219-220° C.

EXAMPLE 52 N-(1-Naphthylmethyl)-N-(4-tert-butylbenzyl)guanidine.HCl((1-C₁₀H₇CH₂)(4-(C(CH₃)₃C₆H₄CH₂)NC(═NH)NH₂).HCl)

¹H NMR (CDCl₃): δ ppm 7.95-7.10 (m, ArH, 11H), 5.10 (s, CH₂, 2H), 4.58(s, CH₂, 2H), 1.32 (s, CH₃, 9H); MS(El): m/e 346 (M⁺: C₂₃H₂₇N₃); Anal.(C₂₃H₂₇N₃.HCl.H₂O): Calcd. (%): C, 69.07, H, 7.56, N, 10.51; Found (%):C, 68.70, H, 7.71, N, 10.19; TLC: R_(f)=0.50 (SiO₂, CH₂Cl₂/MeOH=9/1);mp: 134-135° C.

EXAMPLE 53 N-(5-Acenaphthyl)-N-(3-phenoxybenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.62-6.80 (m, ArH, 14H), 5.20 (d, CH₂, J=15.7 Hz,1H), 4.70 (d, CH₂, J=15.9 Hz, 1H), 3.46-3.40 (m, CH₂, 4H); MS(El): m/e393.5 (M⁺: C₂₆H₂₃ON₃); Anal. (C₂₆H₂₃ON₃.HCl): Calcd. (%): C, 72.63, H,5.63, N, 9.77; Found (%): C, 72.77, H, 5.57, N, 9.67; TLC: R_(f)=0.45(SiO₂, CH₂Cl₂/MeOH=10/1); mp: 100-101° C.

EXAMPLE 54N-(3-Trifluoromethylphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.63-7.13 (m, ArH, 8H), 4.92 (s, ArCH₂, 2H), 1.29(s, CH₃, 9H); MS(EI): m/e 349.1 (M⁺: C₁₉H₂₂F₃N₃); Anal.(C₁₉H₂₂F₃N₃.HCl): Calcd. (%): C, 59.14, H, 6.01, N, 10.89; Found (%): C,59.14, H, 6.12, N, 10.88; TLC: R_(f)=0.49 (SiO₂, CH₂Cl₂/MeOH=10/1); mp:281-282° C.

EXAMPLE 55 N-(3-Methylthiophenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

¹H NMR CCD₃OD): δ ppm 7.42-7.15 (m, ArH, 8H), 4.87 (s, ArCH₂, 2H), 235(s, SCH₃, 3H), 1.30 (s, CH₃, 9H); MS(EI): m/e 327.3 (M⁺: C₁₉H₂₅SN₃);Anal. (C₁₉H₂₅SN₃.HCl): Calcd. (%): C. 62.70, H, 7.20, N, 11.55; Found(%): C, 62.81, H, 7.27, N, 11.57; TLC: R_(f)=0.37 (SiO₂,CH₂Cl₂/MeOH=10/1); mp: 247-248° C.

EXAMPLE 56 N-(5-Acenaphthyl)-N-(3-iodobenzyl)guanidine.HCl

¹H NMR (CDCl₃): δ ppm 7.62-7.00 (m, ArH, 9H), 5.46 (d, CH₂, J=0.55 Hz,1H), 4.75 (d, CH₂, J=1.98 Hz, 1H), 3.49-3.42 (m, CH₂, 4H); MS(El): m/e427.1 (M⁺: C₂₀H₁₈lN₃); Anal. (C₂₀H₁₈N₃.HCl): Calcd. (%): C, 51.80, H,4.13, N, 9.06; Found (%): C, 52.00, H, 4.14, N, 9.00; TLC: R_(f)=0.46(SiO₂, CH₂Cl₂/MeOH=10/1); mp: 249-250° C.

EXAMPLE 57 N-(5-Acenaphthyl)-N-(cinnamyl)guanidine.HCl

¹H NMR (CDCl₃): δ ppm 7.62-7.18 (m, ArH, 10H), 6.65 (d, CH₂, J=15.66 Hz,1H), 6.30 (dd, CH₂, J=15.5 Hz, 1H), 5.27 (m, ═CH, 0.5H), 4.92 (m, ═CH,0.5H), 4.40 (m, ═CH, 1H), 3.57-3.41 (m, CH₂, 4H); MS(El): m/e 327.2 (M⁺:C₂₂H₂₁N₃); Anal. (C₂₂H₂₁N₃.HCl.3/4H₂O): Calcd. (%): C, 70.01, H, 6.27,N, 11.13; Found (%): C, 70.21, H, 6.31, N, 11.10; TLC: R_(f)=0.46 (SiO₂,CH₂Cl₂/MeOH=10/1); mp: 205-206.5° C.

EXAMPLE 58 N-(5-Acenaphthyl)-N-(4-iodobenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.65-7.00 (m, ArH, 9H), 5.20 (d, CH₂, J=15.7 Hz,1H), 4.70 (d, CH₂, J=15.9 Hz, 1H), 3.46-3.40 (m, CH22, 4H); MS(El): m/e427.2 (M⁺: C₂₀H₁₈lN₃); Anal. (C₂₀H₁₈lN₃.HCl.3/2H₂O): Calcd. (%): C,48.95, H, 4.52, N, 8.56; Found (%): C, 48.62, H, 4.42, N, 8.39; TLC:R_(f)=0.43 (SiO₂, CH₂Cl₂/MeOH=10/1); mp: 269-270° C.

EXAMPLE 59 N-(5-Acenaphthyl)-N-(4-trifluaromethoxybenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.567.17 (m, ArH, 9H), 5.25 (d, CH₂, J=15.9 Hz,1H), 4.82 (d, CH₂, J=15.7 Hz, 1H), 3.43-3.41 (m, CH₂, 4H); MS(El): m/e385.3 (M⁺: C₂₁H₁₈F₃ON₃); Anal. (C₂₁H₁₈F₃ON₃.HCl.2H₂O): Calcd. (%): C,55.09, H, 5.06, N, 9.18; Found (%): C, 55.33, H, 4.78, N, 9.08; TLC:R_(f)=0.53 (SiO₂, CH₂Cl₂/MeOH=10/1); mp: 120-122° C.

EXAMPLE 60N-(5-Acenaphthyl)-N′-((4-tert-butylphenyl)-(4-sec-butylphenyl)-N′-methylguanidine.HCl

¹H NMR (CD₃OD): δ ppm 8.20-7.15 (m, ArH, 13H), 6.10 (d, CH, 1H),3.43-3.41 (m, CH₂, 4H), 2.62 (m, CH, 1H), 1.59 (m, CH₂, 2H), 1.29 (s,CH₃, 9H), 1.21 (d, CH₃, J=7.0 Hz, 3H), 0.8 (t, CH₃, J=7.0 Hz, 3H);MS(EI): m/e 489.4 (M⁺: C₃₄H₃₉N₃); Anal. (C₃₄H₃₉N₃.HCl): Calcd. (%): C,77.61, H, 7.66, N, 7.99; Found (%): C, 77.43, H, 7.45, N, 7.97; TLC:R_(f)=0.5 (SiO₂, CH₂Cl₂/MeOH=10/1); mp: 173-174° C.

EXAMPLE 61 N-(4-Butoxyphenyl)-N,N′-bis(4-tert-butylbenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.50-6.60 (m, ArH, 12H), 4.90 (s, CH₂ 2H), 4.43(s, CH₂ 2H), 3.97 (t, CH₂, J=6.4 Hz, 2H), 1.73 (m, CH₂, 2H), 1.49 (m,CH_(2, 2)H), 1.31 (s, CH₃, 18H), 0.94 (t, CH₃, J=7.4 Hz, 3H); MS(EI):m/e 499.3 (M⁺: C₃₃H₄₅N₃O₁); Anal. (C₃₃H₄₅N₃O₁.HCl): Calcd. (%): C,73.92, H, 8.65, N, 7.84; Found (%): C, 73.87, H, 8.46, N, 7.91; TLC:R_(f)=0.4 (SiO₂, CH₂Cl₂/MeOH=10/1); mp: 112-113° C.

EXAMPLE 62 N-(3-sec-Butylphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.38-6.81 (m, ArH, 8H), 4.86 (s, ArCH₂, 2H), 2.53(m, CH, 1H), 1.45 (m, CH₂, 2H), 1.29 (s, CH₃, 9H), 1.12 (d, CH₃, J=6.93Hz, 3H), 0.71 (t, CH₃, J=7.37 Hz, 3H); MS(El): m/e 337.4 (M⁺: C₂₂H₃₁N₃);Anal. (C, H, N; C₂₂H₃₁N₃.HCl.0.5H₂O): Calcd. (%): C, 68.79, H, 8.68, N,10.97; Found (%): C, 69.23, H, 8.35, N, 10.92; TLC: R_(f)=0.46 (SiO₂,CH₂Cl₂/MeOH=10/1); mp: 190-191° C.

EXAMPLE 63 N-(3-tert-Butylphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

¹H NMR (CDCl₃): δ ppm 7.51-7.19 (m, ArH, 8H), 4.92 (s, ArCH₂, 2H), 1.34(s, CH₃, 9H), 1.31 (s, CH₃, 9H); MS(El): m/e 337.4 (M⁺: C₂₂H₃₁N₃); Anal.(C, H, N; C₂₂H₃₁N₃.HCl); Calcd. (%): C, 70.66, H, 8.62, N, 11.24; Found(%): C, 70.50, H, 8.55, N, 11.29; TLC: R_(f)=0.45 (SiO₂,CH₂Cl₂/MeOH=10/1); mp: 291-292° C.

EXAMPLE 64 N-(3-Pentoxyphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.41-7.20 (m, ArH, 8H), 4.93 (s, ArCH₂, 2H), 3.90(t, OCH₂, J=6.49 Hz, 2H), 1.78-1.60 (m, CH₂, 2H), 1.44-1.40 (m, 2CH₂,4H), 1.31 (s, CH₃, 9H), 0.94 (t, CH₃, J=6.98 Hz, 3H); MS(EI): m/e 367.3(M⁺: C₂₃H₃₃N₃O); Anal. (C, H, N; C₂₃H₃₃N₃O.HCl.0.5H₂O); Calcd. (%): C,66.89, H, 8.54, N, 10.17; Found (%): C, 66.98, H, 8.33, N, 10.05; TLC:R_(f)=0.51 (SiO₂, CH₂Cl₂/MeOH=10/1); mp: 198-199° C.

EXAMPLE 65 N-(5-Acenaphthyl)-N-(4-benzyloxybenzyl)guanidine.HCl((5-C₁₂H₉)(4-(C₆H₅CH₂O)C₆H₄CH₂)NC(═NH)NH₂).HCl)

¹H NMR (CDCl₃): δ ppm 7.56-6.86 (m, ArH, 14H), 5.31 (d, CH₂, J=15.02 Hz,1H), 5.02 (s, CH₂, 2H), 4.70 (d, CH₂, J=15.41 Hz, 1H), 3.50-3.41 (m,2CH₂, 4H); MS(EI): m/e 407.3 (M⁺: C₂₇H₂₅N₃O); Anal. (C, H, N;C₂₇H₂₅N₃O.HCl); Calcd. (%): C, 73.04, H, 5.90, N, 9.46; Found (%): C,72.93, H, 5.68, N, 9.30; TLC: R_(f)=0.51 (SiO₂, CH₂Cl₂/MeOH=10/1); mp:118-119° C.

EXAMPLE 66 N-(4-sec-Butylphenyl)-N-(4-benzyloxybenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.39-6.92 (m, ArH, 13H), 5.05 (s, OCH₂, 2H), 4.82(s, CH₂, 2H), 2.62 (m, CH, 1H), 1.60 (m, CH₂, 2H), 1.21 (d, CH₃, J=6.96Hz, 3H), 0.81 (t, CH₃, J=7.4 Hz, 3H); MS(EI): m/e 387.3 (M⁺: C₂₅H₂₉N₃O);Anal. (C, H, N.; C₂₅H₂₉N₃O.HCl.0.6H₂O); Calcd.(%): C, 69.06, H, 7.23, N,9.66; Found (%): C, 68.86, H, 6.83, N, 9.80; TLC: R_(f)=0.48 (SiO₂,CH₂Cl₂/MeOH=10/1); mp: 84-85° C.

EXAMPLE 67 N-(4-Benzyloxyphenyl)-N-(4-benzyloxybenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.40-6.93 (m, ArH, 18H), 5.08 (s, OCH₂, 2H), 5.06(s, OCH₂, 2H), 4.79 (s, CH₂, 2H); MS(El): m/e 437.2 (M⁺: C₂₈H₂₇N₃O₂);Anal. (C, H, N; C₂₈H₂₇N₃O₂.HCl); Calcd.(%): C, 70.95, H, 5.95, N, 8.86;Found (%): C, 70.81, H, 5.71, N, 8.71; TLC: R_(f)=0.44 (SiO₂,CH₂Cl₂/MeOH=10/1); mp: 193-194° C.

EXAMPLE 68 N-(5-Acenaphthyl)-N-(3-benzyloxybenzyl)guanidine.HCl

¹H NMR (CDCl₃): δ ppm 7.45-6.55 (m, ArH, 14H), 5.25-5.45 (m, CH₂, 1H),4.86 (s, CH₂, 2H), 4.45-4.65 (d, CH₂, 1H), 3.25-3.50 (m, 2CH₂, 4H);MS(El): m/e 407.4 (M⁺: C₂₇H₂₅N₃O); Anal. (C, H, N; C₂₇H₂₅N₃O.HCl.H₂O);Calcd. (%): C, 70.20, H, 6.11, N, 9.10; Found (%): C, 70.42, H, 6.00, N,9.18; TLC: R_(f)=0.38 (SiO₂, CHCl₃/MeOH=10/1); mp: 140-141° C.

EXAMPLE 69 N-(4-Isopropylphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.12-7.41 (m, ArH, 8H), 4.88 (s, CH₂, 2H),2.80-3.00 (m, CH, 1H), 1.30 (s, CMe₃, 9H), 1.23 (d, CH₃, J=6.9 Hz, 3H);MS(El): m/e 324 (M⁺: C₂₁H₂₉N₃); HRMS: 323.2366 (Calcd. 323.2361); Anal.(C, H, N; C₂₁H₂₉N₃.HCl); Calcd. (%): C, 70.08, H, 8.40, N, 11.67; Found(%): C, 69.85, H,8.24, N,11.90; TLC: R_(f)=0.64 (SiO₂, CHCl₃/MeOH=10/1);HPLC: 100%; mp: 260-261° C.

EXAMPLE 70 N-(4-Benzyloxyphenyl)-N-(4-tert-butylbenzyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.00-7.50 (m, ArH, 13H), 5.08 (s, OCH₂, 2H), 4.84(s, CH₂, 2H), 1.30 (s, CMe₃, 9H); MS(EI): m/e 388 (M⁺: C₂₅H₂₉N₃O); HRMS:387.2315 (Calcd.: 387.2311); TLC: R_(f)=0.49 (SiO₂, CHCl₃/MeOH 10/1);HPLC: 99.8%; mp: 178-179° C.

EXAMPLE 71 N-(4-Hexylphenyl)-N-(4-hexylbenzyl)guanidine.mesylate

¹H NMR (CD₃OD): δ ppm 7.05-7.30 (m, ArH, 8H), 4.86 (s, CH₂, 2H), 2.69(s, CH₃SO₃H, 3H), 2.55-2.64 (m, 2CH₂, 4H), 1.50-1.70 (m, 2CH₂, 4H),1.25-1.40 (m, 6CH₂, 12H), 0.80-1.00 (m, CH₃, 6H); MS(El): m/e 493.4 (M⁺:C₂₆H₃₉N₃); HRMS: 393.3166 (Calcd: 393.3160); TLC: R_(f)=0.52 (SiO₂,CHCl₃/MeOH=10/1); HPLC: 99.7%; mp: oil.

EXAMPLE 72N-(4-sec-Butylphenyl)-N-(4-t-butylbenzyl)-N′-pyrrolidinylguanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.50-7.15 (m, ArH, 8H), 4.95 (s, CH₂, 2H),3.25-3.15 (m, CH₂, 4H), 2.65-2.50 (m, CH, 1H), 1.80-1.90 (m, CH₂, 4H),1.68-1.55 (m, CH₂, 2H), 1.31 (s, t-butyl, 9H), 1.23 (d, CH₃; J=7.0 Hz,3H), 0.79 (t, CH₃, J=7.4 Hz, 3H); HRMS(El): m/e 391.2991 (Calcd.391.2987 for C₂₆H₃₇N₃); TLC: R_(f)=0.4 (SiO₂, CHCl₃/MeOH=10/1); HPLC:96% pure; mp: 98-100° C.

EXAMPLE 73N-(4-sec-Butylphenyl)-N-(4-t-butylbenzyl)-N′-(4-thiomorpholinyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.50-7.18 (m, ArH, 8H), 4.97 (s, CH₂, 4H),3.15-3.05 (m, CH₂, 4H), 2.70-2.60 (m, CH, 1H), 2.40-2.25 (m, CH₂, 4H),1.68-1.56 (m, CH₂, 2H), 1.31 (s, t-butyl, 9H), 1.23 (d, CH₃, J=7.0 Hz,3H), 0.79 (t, CH₃, J=7.4 Hz, 3H); HRMS(EI): m/e 423.2722 (Calcd.423.2708 for C₂₆H₃₇S₁N₃); Anal. (C₂₆H₃₇S₁N₃.HCl); Calcd (%): C, 67.87,H, 8.32, N, 9.13; Found (%): C, 67.85, H, 8.11, N, 9.36; TLC: R_(f)=0.4(SiO₂, CHCl₃/MeOH=10/1); HPLC: 98.6% pure; mp: 70-72° C.

EXAMPLE 74N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-piperidinylguanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.50-7.16 (m, ArH, 8H), 4.96 (s, CH₂, 2H), 2.62(m, CH, 1H), 1.70-1.40 (m, 6CH₂, 12H), 1.31 (s, CH₃, 9H), 1.22 (d, CH₃,J=6.93 Hz, 3H), 0.79 (t, CH₃, J=7.39 Hz, 3H); HRMS: 405.3138 (Calcd:405.3144 for C₂₇H₃₉N₃); HPLC: 99.80%; TLC: R_(f)=0.47 (SiO₂,CH₂Cl₂/MeOH=10/1); mp: 217-218° C.

EXAMPLE 75N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-morpholinyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.21-7.46 (m, ArH, 8H), 4.99 (s, CH₂, 2H),3.41-3.45 (m, 20CH₂, 4H), 3.30-3.31 (m, NCH₂, 4H), 2.55-2.70 (m, CH,1H), 1.59-1.62 (m, CH₂, 2H), 1.31 (s, CMe₃, 9H), 1.23 (d, CH₃, J=7.0 Hz,3H), 0.79 (t, CH₃, J=7.4 Hz, 3H); MS(EI): m/e 408 (M⁺: C₂₆H₃₇N₃O); Anal.(C, H, N; C₂₆H₃₇N₃O.HCl.0.75H₂O); Calcd. (%): C, 68.24, H, 8.70, N,9.18; Found (%): C, 67.76, H, 8.56, N, 9.08; TLC: R_(f)=0.43 (SiO₂,CHCl₃/MeOH=10/1); HPLC: 98.57%; mp: 220-221° C.

EXAMPLE 76N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-propylpiperidinyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.16-7.46 (m, ArH, 8H), 4.94 (s, CH₂, 2H),3.70-3.90 (m, ring-H, 2H), 2.80-2.95 (m, ring-H, 3H), 2.55-2.70 (m, CH,1H), 0.59-2.70 (m, ring-4H; CMe₃, 9H; 3CH₃, 9H; 3CH₂, 6H); MS(EI): m/e448 (M⁺: C₃₀H₄₅N₃); Anal. (C, H, N; C₃₀H₄₅N₃.HCl.1.25H₂O); Calcd. (%):C, 71.11, H, 9.65, N, 8.29; Found (%): C, 71.13, H, 9.50, N, 8.53; TLC:R_(f)=0.64 (SiO₂, CHCl3/MeOH=10/1); HPLC: 93.1 %; mp: 109-110° C.

EXAMPLE 77N-(4-Butoxyphenyl)-N-(4-tert-butylbenzyl)-N′-(4-piperidinyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 6.94-7.45 (m, ArH, 8H), 4.91 (s, CH₂, 2H), 3.97(t, OCH₂, J=6.36 Hz, 2H), 1.70-1.85 (m, CH₂, 2H), 1.25-1.60 (m, ring-H,10H; CMe₃, 9H; CH₂, 2H), 0.98 (t, CH₃, J=7.4 Hz, 3H); MS(El): m/e 422.3(M⁺: C₂₇H₃₉N₃O); HRMS: 421.3110 (Calcd.: 421.3093); TLC: R_(f)=0.28(SiO₂, CHCl₃/MeOH=10/1); HPLC: 93.7%; mp: 99-100° C.

EXAMPLE 78N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-benzylpiperidinyl)guanidine.mesylate

¹H NMR (CD₃OD): δ ppm 7.03-7.46 (m, ArH, 13H), 4.94 (s, CH₂, 2H),3.70-3.90 (m, ring-H, 3H), 2.77-2.95 (m, ring-H, 3H), 2.70 (s, CH₃SO₃H,3H), 2.60-2.70 (m, CH, 1H), 2.40 (d, CH₂, J=7.15 Hz, 2H), 1.55-1.75 (m,CH₂, 2H), 1.40-1.55 (m, ring-H, 3H), 1.31 (m, CMe3, 9H), 1.24 (d, CH₃,J=6.93 Hz, 3H), 0.82 (t, CH₃, J=7.4 Hz, 3H); MS(El): m/e 495.3 (M⁺:C₃₄H₄₅N₃); HRMS: 495.3604 (Calcd.: 495.3613); TLC: R_(f)=0.55 (SiO₂,CHCl₃/MeOH=10/1); HPLC: 94.7%; mp: 85-86° C.

EXAMPLE 79N-(4-Benzyloxyphenyl)-N-(4-tert-butylbenzyl)-N′-(4-morpholinyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.00-7.50 (m, ArH, 13H), 5.10 (s, OCH₂, 2H), 4.94(s, CH₂, 2H), 3.41-3.50 (m, 20CH₂, 4H), 3.25-3.35 (m, NCH₂, 4H), 1.31(s, CMe₃, 9H); MS(EI): m/e 457.4 (M⁺: C₂₉H₃₅N₃O₂): Anal. (C, H, N;C₂₉H₃₅N₃O₂.HCl); Calcd. (%): C, 70.50, H, 7.34, N, 8.50; Found (%): C,70.29, H, 7.15, N, 8.36; TLC: R_(f)=0.50 (SiO₂, CHC₃/MeOH=10/1); HPLC:95%; mp: 75-77° C.

EXAMPLE 80N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(1,2,3,4-tetrahydroisoquinolinyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 6.95-7.50 (m, ArH, 12H), 5.01 (s, benzylic-CH₂,2H), 4.46 (s, benzylic-CH₂N, 2H), 3.60 (t, CH₂, J=6 Hz, 2H), 2.55-2.70(m, CH, 1H), 2.48 (t, CH₂, J=6.0 Hz, 2H), 1.50-1.65 (m, CH₂, 2H), 1.30(s, CMe₃, 9H), 1.20 (d, CH₃, J=6.93 Hz, 3H), 0.77 (t, CH₃, J=7.4 Hz,3H); MS(EI): m/e 454.4 (M⁺: C₃₁H₃₉N₃); HRMS: 453.3165 (Calcd.:453.3144); TLC: R_(f)=0.51 (SiO₂, CHCl₃/MeOH=10/1); HPLC: 100%; mp:217-218° C.

EXAMPLE 81N-(3-Butoxy-4-methoxyphenyl)-N-(4-tert-butylbenzyl)-N′-(4-morpholinyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 6.55-7.50 (m, ArH, 7H), 4.93 (s, CH₂, 2H),3.80-3.90 (m, OCH₂+OCH₃, 5H), 3.45-3.55 (m, 20CH₂, 4H), 3.30-3.40 (m,NCH₂, 4H), 1.65-1.80 (m, CH₂, 2H), 1.40-1.55 (m, CH₂, 2H), 1.31 (s,CMe₃, 9H), 0.97 (t, CH₃, J=7.4 Hz, 3H); MS(EI): m/e 453.4 (M⁺:C₂₇H₃₉N₃O₃); HRMS: 453.3010 (Calcd.: 453.2991); TLC: R_(f)=0.39 (SiO₂,CHCl₃/MeOH=10/1); HPLC: 98%; mp: 197-199° C.

EXAMPLE 82N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(3,5-dimethyl-4-morpholinyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.20-7.50 (m, ArH, 8H), 4.99 (s, CH₂, 2H),3.55-3.70 (m, 20CH, 2H), 3.15-3.25 (m, NCH₂, 2H), 2.50-2.70 (m, CH+NCH₂,3H), 1.55-1.70 (m, CH₂, 2H), 1.30 (s, CMe₃, 9H), 1.23 (d, CH₃, J=6.93Hz, 3H), 0.99 (m, 2CH₃, 6H), 0.79 (m, CH₃, 3H); MS(EI): m/e 435.5 (M⁺:C₂₈H₄₁N₃O); TLC: R_(f)=0.51 (SiO₂, CHCl₃/MeOH=10/1); HPLC: 98.7%; mp:98-99° C.

EXAMPLE 83N-(4-tert-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-sec-butylphenyl)-N′-(methyl)guanidine.HCl

¹H NMR (CDCl₃): δ ppm 7.42-6.60 (m, ArH, 12H), 4.92 (s, CH₂, 2H), 3.56(s, CH₃, 3H), 2.52 (m, CH, 1H), 1.54 (m, CH₂, 2H), 1.33 (s, CH₃, 9H),1.26 (s, CH₃, 9H), 1.17 (d, CH₃, J=7.14 Hz, 3H), 0.80 (t, CH₃, J=7.28Hz, 3H); MS(EI): m/e 483.5 (M⁺: C₃₃H₄₅N₃); Anal. (C, H, N:C₃₃H₄₅N₃.HCl); Calcd. (%): C, 76.19, H, 8.91, N, 8.08; Found (%): C,76.12, H, 8.87, N, 8.03; TLC: R_(f)=0.53 (SiO₂, CH₂Cl₂/MeOH=10/1); mp:111-112° C.

EXAMPLE 84N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-sec-butylphenyl)-N′-(methyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.50-6.70 (m, ArH, 12H), 4.88 (s, CH₂, 2H), 3.35(s, CH₃, 3H), 2.50 (m, 2CH, 2H), 1.54 (m, 2CH₂, 4H), 1.30 (s, CH₃, 9H),1.15 (m, 2CH₃, 6H), 0.80 (m, 2CH₃, 6H); MS(EI): m/e 483.5 (M⁺:C₃₃H₄₅N₃); Anal. (C, H, N; C₃₃H₄₅N₃.HCl); Calcd. (%): C, 76.19, H, 8.91,N, 8.08; Found (%): C, 75.94; H, 9.07, N, 7.86; TLC: R_(f)=0.30 (SiO₂,CH₂Cl₂/MeOH=10/1); mp: 106-107° C.

EXAMPLE 85N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(phenyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.50-7.23 (m, ArH, 13H), 5.03 (s, CH₂, 2H), 2.62(m, CH, 1H), 1.60 (m, CH₂, 2H), 1.30 (s, CH₃, 9H), 1.15 (d, CH₃, J=6.96Hz, 3H), 0.80 (t, CH₃, J=7.37 Hz, 3H); HRMS: 413.2818 (Calcd: 413.2831for C₂₈H₃₅N₃); HPLC: 96.80%; TLC: R_(f)=0.58 (SiO₂, CH₂Cl₂/MeOH=10/1);mp: 204-205° C.

EXAMPLE 86N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-chlorophenyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.22-7.46 (m, ArH, 12H), 5.02 (s, CH₂, 2H),2.55-2.70 (M, CH, 1H), 1.59-1.62 (m, CH₂, 2H), 1.30 (s, CMe₃, 9H), 1.20(d, CH₃, J=6.9 Hz, 3H), 0.80 (t, CH₃, J=7.4 Hz, 3H); MS(EI): m/e 447.7(M⁺: C₂₈H₃₄N₃ClC); HRMS: 447.2412 (Calcd. 447.2441); Anal. (C, H, N;₂₈H₃₄N₃Cl.HCl.0.5H₂O); Calcd. (%): C, 68.15, H, 7.35, N, 8.51; Found(%): C, 68.15, H, 7.44, N, 8.50; TLC: R_(f)=0.40 (SiO₂,CHCl₃/MeOH=10/1); mp: 98-99° C.

EXAMPLE 87N-(4-Butoxylphenyl)-N-(4-tert-butylbenzyl)-N′-(phenyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 6.94-7.47 (m, ArH, 13H), 4.99 (s, CH₂, 2H), 3.97(t, OCH₂, J=6.43 Hz, 2H), 2.55-2.70 (m, CH, 1H), 1.65-1.80 (m, CH₂, 2H),1.40-1.55 (m, CH₂, 2H), 1.31 (s, CMe₃, 9H), 0.96 Ct, CH₃, J=7.4 Hz, 3H);MSC(EI): m/e 430 (M⁺: C₂₈H₃₅N₃O); Anal. (C, H, N;C₂₈H₃₅N₃O.HCl.0.75H₂O); Calcd. (%): C, 70.13, H, 7.88, N, 8.76; Found(%): C, 70.29, H, 7.53, N, 9.12; TLC: R_(f)=0.26 (SiO₂,CHCl₃/MeOH=10/1); HPLC: 97.1%; mp: 95-96° C.

EXAMPLE 88N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(phenyl)-N′-methylguanidine.HCl

¹H NMR (CD₃OD): δ ppm 6.79-7.44 (m, ArH, 13H), 4.88 (s, CH₂, 2H), 3.35(s, CH₃, 3H), 2.45-2.60 (m, CH, 1H), 1.45-1.62 (m, CH₂, 2H), 1.30 (s,CMe₃, 9H), 1.15 (d, CH₃, J=6.9 Hz, 3H), 0.77 (t, CH₃, J=7.4 Hz, 3H);MS(EI): m/e 427.1 (M⁺: C₂₉H₃₇N₃); HRMS: 427.2987 (Calcd.: 427.2954);Anal. (C, H, N; C₂₉H₃₇N₃.HCl); Calcd. (%): C, 75.05, H, 8.25, N, 9.05;Found (%): C, 74.91, H, 8.12, N, 9.11; TLC: R_(f)=0.56 (SiO₂,CHCl₃/MeOH=10/1); mp: 80-82° C.

EXAMPLE 89N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(3,4-dichlorophenyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.21-7.57 (m, ArH, 11H), 5.04 (s, CH₂, 2H),2.55-2.70 (m, CH, 1H), 1.50-1.65 (m, CH₂, 2H), 1.30 (s, CMe₃, 9H), 1.20(d, CH₃, J=6.9 Hz, 3H), 0.79 (t, CH₃, J=7.4 Hz, 3H); MS(EI): m/e 482.1(M⁺: C₂₈H₃₃N₃Cl₂); HRMS: 481.2025 (Calcd.: 481.2052); Anal. (C, H, N;C₂₈H₃₃N₃Cl₂.HCl); Calcd. (%): C, 64.80, H, 6.60, N, 8.10; Found (%): C,64.78, H, 6.58, N, 8.14; TLC: R_(f)=0.71 (SiO₂, CHCl₃/MeOH=10/1); mp:168-169° C.

EXAMPLE 90N-(4-Hexylphenyl)-N-(4-tert-hexylbenzyl)-N′-phenylguanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.15-7.70 (m, ArH, 13H), 5.01 (s, CH₂, 2H),2.55-2.70 (m, 2CH₂, 4H), 1.50-1.70 (m, 2CH₂, 4H), 1.25-1.40 (m, 6CH₂,12H), 0.80-1.00 (m, CH₃, 6H); MS(EI): m/e 469.4 (M⁺: C₃₂H₄₃N₃); HRMS:469.3476 (Calcd.: 469.3457); TLC: R_(f)=0.56 (SiO₂, CHCl₃/MeOH=10/1);HPLC: 100%; mp: oil.

EXAMPLE 91N-(4-sec-Butylphenyl)-N-(4-tert-butylbenzyl)-N′-(4-benzyloxyphenyl)guanidine.mesylate

¹H NMR (CD₃OD): δ ppm 7.05-7.50 (m, ArH, 17H), 5.11 (s, OCH₂, 2H), 5.00(s, CH₂, 2H), 2.69 (s, CH₃SO₃H, 3H), 2.55-2.70 (m, CH, 1H), 1.50-1.70(m, CH₂, 2H), 1.30 (s, CMe₃, 9H), 1.20 (d, CH₃, J=6.9 Hz, 3H), 0.80 (t,CH₃, J=7.4 Hz, 3H); MS(El): m/e 519.5 (M⁺: C₃₅H₄₁N₃O); Anal. (C, H, N;C₃₅H₄₁N₃O.CH₃SO₃H); Calcd. (%): C, 70.21, H, 7.37, N, 6.82; Found (%):C, 70.12, H, 7.16, N, 6.69; TLC: R_(f)=0.53 (SiO₂, CHCl₃/MeOH=10/1);HPLC: 96.9%; mp: 142-143° C.

EXAMPLE 92 N,N′-Bis-(4-tert-butylphenyl)-N,N′-methylguanidine.HBr

White solid; mp: 175-177° C.; TLC (CH₂Cl₂:MeOH; 10:1); R_(f)=0.39; ¹HNMR (CD₃OD): 7.21-7.18 (d, J=8.52 Hz, 4H, ArH), 6.80-6.78 (d, J=8.51 Hz,4H, ArH), 3.35 (s, 6H, —CH₃), 1.26 (s, 18H, —C(CH₃)₃); Anal. Calcd. forC₂₃H₃₃N₃.HCl (388.00); C, 71.20, H, 8.83, N, 10.83; Found: C, 70.88, H,8.61, N, 10.75.

EXAMPLE 93 N-(4-Benzyloxyphenyl)-N′-(4-tert-butylphenyl)guanidine.HCl

White solid; mp: 143-144° C.; TLC (CH₂Cl₂:MeOH; 15:1); R_(f)=0.35; ¹HNMR (CD₃OD): 7.547-7.089 (m, 13H, ArH), 5.135 (s, CH₂, 2H), 1.346 (s,t-butyl, 9H); Anal. Calcd. for C₂₄H₂₈N₃ClO (409.96): C, 70.32, H, 6.88,N, 10.25; Found: C, 70.49, H, 6.94, N, 10.09.

EXAMPLE 94 N,N′-Bis-(3-(1′-methyl-2′-phenyl)ethyl)guanidine.HCl

White solid; mp: 93-95° C.; TLC (CH₂Cl₂:MeOH; 15:1); R_(f)=0.41; ¹H NMR(CD₃OD): 7.395-7.344 (t, J=8.69 Hz, 2H, ArH), 7.225-7.077 (m, 16H, ArH),3.092-3.045 (m, CH, 2H), 2.952-2.827 (m, CH₂, 4H), 1.273-1.250 (d,J=6.87 Hz, 6H); Anal. Calcd. for C₃₁H₃₄N₃Br.1/2H₂O (537.55): C, 69.27,H, 6.51, N, 7.81; Found: C, 69.61 H, 6.63, N, 7.87.

EXAMPLE 95N-Methyl-N-4-benzyloxyphenyl-N′-(4-tert-butylphenyl)guanidin.mesylat

White solid; mp: 230-232° C.; TLC (AcOEt:MeOH; 10:1): R_(f)=0.45; ¹HNMR: 7.421-6.961 (m, ArH, 13H), 5.059 (s, OCH₂, 2H), 3.413 (s, N—CH₃,3H), 2.770 (s, CH₃, 3H), 1.286 (s, t-butyl, 9H); Anal. Calcd. forC₂₅H₃₃N₃O₃.S.1/2H₂O (492.63: C, 63.33, H, 6.90, N, 8.53; Found: C,63.48, H, 6.40, N, 8.48.

EXAMPLE 96 N,N′-Bis-(4-Hexylphenyl)guanidine.mesylate

White solid; mp: 92-94° C.; TLC (AcOEt:MeOH; 10:1): R_(f)=0.49; ¹H NMR:7.265-7.172 (m, ArH, 8H), 2.823 (s, CH₃, 3H), 2.627-2.575 (t, CH₂,J=7.695 Hz, 4H), 1.583-1.558 (m, CH₂, 4H), 1.336-1.261 (m, CH₂CH₂, 8H),0.905-0.861 (t, CH₃, J=6.59 Hz, 6H); Anal. Calcd. for C₂₆H₄₁N₃O₃S(475.69): C, 65.65, H, 8.69, N, 8.83; Found: C, 65.17, H, 8.63, N, 8.70.

EXAMPLE 97N-(3-(1-(4′-Ethoxy)benzyl)phenethyl)-N′-(4-tert-butylphenyl)guanidine.mesylate(3-(4-(CH₃CH₂O)C₆H₄CH₂)C₆H₄)(CH₃)CHNHC(═NH)NH(4-(CH₃)₃C)C₆H₄ mesylate)

White solid; mp: 83-85° C.: TLC (AcOEt:MeOH; 10:1): R_(f)=0.49; ¹H NMR:7.465-6.680 (m, ArH, 12H), 3.957-3.888 (m, CH₂, 2H), 2.961 (m, CH, 1H),2.836 (s, CH₃, 2H), 2.825-2.727 (m, CH₂, 2H), 1.322 (s, tert-butyl, 9H),1.361-1.268 (m, CH₂, CH₃, 5H); HRMS: 429.2749 (429.2780 Calcd. forC₂₈H₃₅ON₃).

EXAMPLE 98N-(4-Benzyloxyphenyl)-N′-methyl-N′-(4-tert-butylphenyl)guanidine.mesylate

White solid; mp: 100-101° C.; TLC (AcOEt:MeOH; 10:1): R_(f)=0.46; ¹HNMR: 7.457-7.371 (m, ArH, 7H), 7.199-7.170 (d, ArH, J=8.58 Hz, 2H),7.081-7.052 (d, ArH, J=8.85 Hz, 2H), 6.924-6.894 (d, ArH, J=9.01 Hz,2H), 5.034 (s, CH₂, 2H), 3.456 (s, CH₃, 3H), 3.456 (s, CH₃, 3H), 1.323(s, tert-butyl, 9H); HRMS: 387.2292 (387.2311 Calcd. for C₂₅H₂₉ON₃).

EXAMPLE 99N-(3-(4-tert-Butylbenzyloxy)phenyl)-N′-(4-tert-butylphenyl)guanidine.mesylate

White solid; mp: 88-92° C.; TLC (AcOEt:MeOH; 10:1): R_(f)=0.48; ¹H NMR(CDCl₃): 7.479-7.199 (m, ArH, 10H), 6.909-6.878 (d, ArH, J=8.94 Hz, 2H),5.071 (s, CH₂, 2H), 2.856 (s, —CH₃, integration is 1.5H instead of 3H),1.329 (s, t-butyl, 9H), 1.292 (s, t-butyl, 9H); HRMS: 429.2783 (429.2780Calcd. for C₃₀H₃₁N₃).

EXAMPLE 100N-(3-(1′-Benzylbutyl)phenyl)-N′-(4-tert-butylphenyl)guanidine.mesylate

White solid; mp: 70-73° C.; TLC (AcOEt:MeOH; 10:1): R_(f)=0.78; ¹H NMR(CDCl₃): 7.494-6.759 (m, ArH, 17H), 3.014-2.691 (m, —CH₂, —CH, —CH₃,6H), 1.755-1.168 (m, CH₂CH₂, 4H), 1.331 (s, t-butyl. 9H), 0.896-0.847(t, CH₃, J=7.28 Hz, 3H); HRMS: 413.2840 (413.2831 Calcd. for C₂₈H₃₅N₃).

EXAMPLE 101 N,N′-Bis-(4-butylphenyl)-N-methylguanidine.HCl

White solid; mp: 137-138° C.; TLC (CHCl₃:MeOH; 10:1): R_(f)=0.40; ¹H NMR(CDCl₃): 7.234-7.026 (m, ArH, 8H), 3.618 (s, CH₃, 3H), 2.628-2.535 (m,CH₂, 4H), 1.600-1.493 (m, CH₂, 4H), 1.382-1.280 (m, CH₂, 4H),0.963-0.900 (m, CH₃, 6H); Anal. Calcd. for C₂₂H₃₂N₃Cl: C, 70.66, H,8.62, N, 11.24; Found: C, 70.47, H, 8.04, N, 11.31.

EXAMPLE 102 N,N′-Bis-(4-tert-butylphenyl)-N,N′-dimethylguanidine.HCl

White solid; mp: 134° C.; TLC (CHCl₃:MeOH; 10:1): R_(f)=0.33; ¹H NMR(CDCl₃): 9.460 (s, 2H), 6.923-6.895 (d, ArH, J=6.37 Hz, 4H), 6.668-6.640(d, ArH, J=8.45 Hz, 4H), 3.557 (s, —CH₃, 3H), 2.529-2.479 (t, CH₂,J−7.525 Hz), 1.570-1.470 (m, CH₂, 4H), 1.358-1.283 (m, CH₂, 4H),0.972-0.924 (t, CH₃, J=7.265 Hz, 6H); Anal. Calcd. forC₂₃H₃₄N₃Cl.1/2H₂O: C, 69.52, H, 8.82, N, 10.58; Found: C, 69.38, H,8.52, N, 10.56.

EXAMPLE 103N-(3-Naphthylmethyleneoxyphenyl)-N′-(4-tert-butylphenyl)guanidine.mesylate(3-(C₁₀H₇CH₂O)C₆H₄NHC(═NH)NH(4-(CH₃)₃C)C₆H₅ mesylate)

White solid; mp: 138-146° C.; TLC (CHCl:MeOH; 10:1): R_(f)=0.52; ¹H NMR(CDCl₃): 7.861-7.803 (m, ArH, 4H), 7.516-7.113 (m, ArH, 8H), 6.936-6.881(m, ArH, 3H), 5.222 (s, CH₂, 2H), 2.814 (s, CH₃, 3H), 1.291 (s, t-butyl,9H); Anal. Calcd. for C₂₉H₃₃N₃O₄S: C, 67.03, H, 6.40, N, 8.09; Found: C,67.26, H, 6.64, N, 8.29.

EXAMPLE 104 N-(4-Benzyloxyphenyl)-N′-(4-butylphenyl)guanidine.HCl

White solid; mp: 112° C.; TLC (CHCl₃:MeOH; 10:1): R_(f)=0.50; ¹H NMR(CDCl₃): 7.403-7.206 (m, ArH, 11H), 7.009-7.039 (d, J=8.91 Hz, ArH, 2H),5.068 (s, Ar—CH₂, 2H), 2.638-2.587 (t, J=7.42 Hz. CH₂, 2H), 1.576-1.560(m, CH₂, 2H), 1.371-1.321 (m, CH₂, 2H), 0.938-0.890 (t, CH₃, J=7.36 Hz,3H); Anal. Calcd. for C₂₄H₂₈ClN₃O: C, 70.32, H, 6.88, N, 10.25; Found:C, 70.42, H, 7.00, N, 10.07.

EXAMPLE 105 N,N′-Bis-(4-butylphenyl)-N-butylguanidine.HCl

White solid; mp: 118-119° C.; TLC (CHCl₃:MeOH; 10:1): R_(f)=0.43; ¹HNMR: 7.235, 7.207, 7.033, 7.005 (q, ArH, 4H), 7.127-7.095 (d, J=9.63 Hz,ArH, 4H); Anal. Calcd. for C₂₇H₃₉N₃O₄ (469.62): C, 69.05, H, 8.37, N,8.95; Found: C. 69.25, H, 8.38, N, 9.03.

EXAMPLE 106N-3-(Benzyloxymethyl)phenyl-N′-(4-tert-butylphenyl)guanidine.mesylate

White solid; mp: 66-68° C.; TLC (CHCl₃:MeOH; 10:1): R_(f)=0.56; ¹H NMR(CDCl₃): 7.456-7.170 (m, ArH, 13H), 4.580 (s, CH₂, 2H), 4.529 (s, CH₂,2H), 2.821 (s, CH₃, 3H), 1.303 (s, C(CH₃)₃, 9H); HRMS: 387.2299(387.2229 calculated for C₂₅H₂₉N₂O₂).

EXAMPLE 107N-(3,4-Bis-butyloxyphenyl)-N′-(4-tert-butylphenyl)guanidine.oxalate

White solid; mp: 100-101° C.; TLC (CHCl₃:MeOH; 10:1): R_(f)=0.58; ¹H NMR(CD₃OD): 7.5251-7.5027 (m, ArH, 2H), 7.2692-7.2402 (m, ArH, 2H),7.0079-6.8720 (m, ArH, 3H), 4.0306-3.9880 (t, OCH₂, 4H), 1.7990-1.7404(m, CH₂, 4H), 1.5580-1.5296 (m, CH₂, 4H), 1.3275 (s, C(CH₃)₃, 9H),1.0243-1.9558 (t, CH₃, 6H); HRMS: 411.2886 (411.2886 calculated forC₂₅H₃₇N₃O₂).

EXAMPLE 108N-(3-Benzyloxy)phenyl-N′-(4-tert-butylphenyl)guanidine.mesylate

White solid; mp: 140° C.; TLC (CHCl₃:MeOH; 10:1): R_(f)=0.50; ¹H NMR(CDCl₃): 7.483-7.203 (m, 9H, ArH), 6.920-6.910 (m, 4H, ArH), 5.080 (s,CH₂, 2H), 2.849 (s, CH₃, 3H), 1.585-1.511 (m, NHs), 1.320 (s, —C(CH₃)₃,9H); HRMS: 373.2158 (373.2154 calculated for C₂₄H₂₇N₃O).

EXAMPLE 109 N,N′-Bis-((3-butoxy-4-methoxy)phenyl)guanidine.HBr

White solid; mp: 174° C.; TLC (CHCl₃:MeOH; 10:1): R_(f)=0.43; ¹H NMR(CDCl₃): 6.924-6.852 (m, 6H, ArH), 4.028-3.984 (t, CH₂, J=6.59 Hz, 4H),3.892 (s, CH_(3, 6)H), 1.872-1.798 (m, CH₂, 4H), 1.594-1.472 (m, —CH₂,4H), 1.021-0.972 (t, CH₃, J=7.28 Hz, 6H); HRMS: 415.2470 (415.2471calculated for C₂₃H₃₃N₃O₄).

EXAMPLE 110N-(4-Benzyloxyphenyl)-N-methyl-N′-(4-butylphenyl)guanidine.mesylate

White solid; mp: 178.4-178.8° C.; TLC (CHCl₃:MeOH; 10:1): R_(f)=0.34; ¹HNMR (CDCl₃): 7.390-6.919 (m, ArH, 13H), 5.029 (s, Ar—CH₂, 2H), 3.389 (s,CH₃, 3H), 2.717 (s, CH₃, 3H), 2.552-2.501 (t, J=7.48 Hz, CH_(2, 2)H),1.544-1.493 (m, CH₂, 2H), 1.328-1.254 (m, CH₂, 2H), 0.916-0.867 (t, CH₃,J=7.33 Hz, 3H); HRMS: 387.2311 (387.2285 calculated for C₂₅H₂₉N₃O).

EXAMPLE 111 N,N′-Bis-(6-tetralinyl)guanidine.HBr

White solid; mp: too fluffy to measure; TLC (CHCl₃:MeOH; 10:1):R_(f)=0.50; ¹H NMR (CDCl₃): 7.273-7.002 (m, ArH, 6H), 2.765 (s, 2CH₂,4H), 1.824-1.780 (p, 2CH₂, 4H); Anal. Calcd. for C₂₁H₂₆N₃Br (400.36): C,63.00, H, 6.55, N, 10.50; Found: C, 62.85, H, 6.62, N, 10.53.

EXAMPLE 112 N-(6-Tetralinyl)-N′-(4-tert-butylphenylguanidine.mesylate

Colorless crystal; mp: 53-55° C.; TLC (CHCl₃:MeOH; 10:1): R_(f)=0.45; ¹HNMR (CDCl₃): 7.240-6.967 (m, 7H, ArH), 2.798 (s, CH₃, 3H), 2.736 (s,CH₂, 4H), 2.628-2.577 (t, J=7.47 Hz, CH₂, 2H), 1.790-1.770 (t, 2CH₂,4H), 1.597-1.546 (m, CH₂, 2H), 1.374-1.300 (m, CH₂, 2H), 0.949-0.901 (t,CH₃, J=7.30 Hz, 3H); HRMS: 321.2184 (321.2205 calculated for C₂₁H₂₇N₃).

EXAMPLE 113 N-(5-Acenaphthyl)-N′-(6-benzothiozolyl)guanidine.HCl

Light green solid; mp: ° C.; TLC (CH₂Cl₂:MeOH; 15:1): R_(f)=0.25; ¹H NMR(CD₃OD): 7.639-7.289 (m, ArH, 9H), 3.443-3.403 (m, CH₂CH₂, 4H),2.086-1.756 (m, CH's, 13H); Anal. Calcd for C₂₉H₃₂N₃Cl (458.08): C,76.04, H, 7.04, N, 9.17; Found: C, 75.97, H, 6.88, N, 9.06.

EXAMPLE 114 N-(5-Acenaphthyl)-N′-(6-N-benzylindolinyl)guanidine.mesylate

White solid; mp: 115-125° C.; TLC (AcOEt:MeOH; 10:1): R_(f)=0.27; ¹HNMR: 7.709-7.260 (m, ArH, 13H), 3.469-3.377 (s, CH₂CH₂, 4H), 2.842 (s,CH₃, 3H); Anal. Calcd. for C₂₉H₃₀N₄O₃S (514.64): C, 67.68, H, 5.88, N,10.89; Found: C, 67.51, H, 5.58, N, 10.88.

EXAMPLE 115N-(5-Acenaphthyl)-N′-(4-benzo-2,1,3-thiadizaole)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.33-8.05 (m, ArH, 8H), 3.43-3.50 (m, 4H, CH₂);MS(EI): m/e 345.1 (M⁺: C₁₉H₁₅N₅S); Anal. (C, H, N; 09637512- SPEC Page97 of 125 (08-11-2000) C₁₉H₁₅N₅S.HCl.1/2H₂O): Calcd. (%): C, 58.45, H,4.39, N, 17.95; Found (%): C, 58.62, H, 4.29, N, 17.47; TLC: R_(f)=0.13(SiO₂, CHCl₃/MeOH)=10:1; mp: 173-174° C.

EXAMPLE 116N-(5-Acenaphthyl)-N′-[4-(6-methyl-benzothiazole)phenylguanidine].HCl

¹H NMR (CD₃OD): δ ppm 8.15-8.17 (m, ArH, 2H), 7.36-7.91 (m, ArH, 10H),3.40-3.50 (m, CH₂, 4H), 2.50 (s, CH₃, 1H); MS(EI): m/e 434.1 (M⁺:C₂₇H₂₂N₄S); Anal. (C, H, N; C₂₇H₂₂N₄S.HCl): Calcd. (%): C, 68.85, H,4.92, N, 11.89; Found (%): C, 68.66, H, 4.91, N, 11.86; TLC: R_(f)=0.23(SiO₂, CHCl₃/MeOH)=10:1; mp: 244.5-246° C.

EXAMPLE 117 N-(5-Acenaphthyl)-N′-(1-benz[cd]indolinyl)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 7.90-7.40 (m, ArH, 11H), 5.66 (s, NCH₂, 2H), 3.49(m, 2CH₂, 4H); MS(EI): m/e 349.2 (M⁺: C₂₄H₁₉N₃); Anal. (C, H, N;C₂₄H₁₉N₃HCl): Calcd. (%6: C, 74.70, H, 5.22, N, 10.89; Found (%): C,74.61, H, 5.08, N, 10.63: TLC: R_(f)=0.51 (SiO₂, CH₂Cl₂/MeOH=10/1); mp:245-246° C.

EXAMPLE 118 N-(5-Acenaphthyl)-N′-(6-banz[cd]indo-2[1H]-one)guanidine.HCl

¹H NMR (CD₃OD): δ ppm 8.25-7.04 (m, ArH, 10H), 3.45-3.43 (m, CH₂, 4H);MS(EI): m/e 378.3 (M⁺: C₂₄H₁₈ON₄); Anal. (C, H, N; C₂₄H₁₈ON₄.HCl):Calcd. (%): C, 69.48, H, 4.62, N, 13.50; Found (%): C, 69.36, H, 4.72,N, 13.27; TLC: R_(f)=0.26 (SiO₂, CH₂Cl₂/MeOH=10/1); mp: 327-328° C.

EXAMPLE 119 N,N′-Bis(6-benz[cd]indolinyl-2[1H]-one)guanidine.HBr

¹H NMR (DMSO): δ ppm 11.00-7.00 (m, ArH, 10H); MS(EI): m/e 393.2 (M⁺:C₂₃H₁₅N₅SO₂); Anal. (C, H, N; C₂₄H₁₈N₄O.HCl): Calcd. (%): C, 58.24, H,3.40, N, 14.77; Found (%): C, 58.25, H, 3.25, N, 14.80; TLC: R_(f)=0.25(SiO₂, CH₂Cl₂/MeOH=10/1); mp: 390-391° C.

EXAMPLE 120 N-(4-Butoxyphenyl)-N′-(4-chlorophenylethyl)guanidine.HCl(4-(CH₃CH₂CH₂CH₂O)C₆H₄NHC(═NH)NH((4-(Cl)C₆H₄)CH₂CH₂).HCl)

Purple solid: mp: 163-164° C.: R_(f)=0.026 (9:1 EtOAc:MeOH); ¹H NMR (300MHz, CD₃OD): δ 7.23-7.38 (m, 4H, ArH), 6.92-7.10 (m, 4H, ArH), 3.95-4.15(t, 2H, CH₂), 3.50-3.58 (t, 2H, CH₂), 2.88-2.93 (m, 2H, CH₂), 1.72-1.81(m, 2H, CH₂), 1.71-1.81 (m, 2H, CH₂), 1.44-1.58 (m, 2H, CH₂), 0.95-1.20(m, 2H, CH₃); MS(CI): m/e 346 (M+ for free base); Anal. Calcd. forC₁₉H₂₄N₃ClO.HC.0.10H₂O: C, 59.40, H, 6.61, N, 10.93; Found: C, 59.15, H,6.31, N, 10.84.

EXAMPLE 121 N-(4-Benzyloxyphenyl)-N,N′-diphenylguanidine.oxalate

White solid: mp: 145° C.; ¹H NMR (300 MHz, CD₃OD): δ 7.30-7.50 (m, 15H,ArH), 7.20-7.25 (d, J=9 Hz, 2H, ArH), 7.02-7.07 (d, 2H, ArH), 5.10 (s,2H, ArCH₂O—); HPLC: 97.6% pure; MS(EI): m/e 393 (M+ for free base);Anal. Calcd. for C₂₆H₂₃N₃O.0.8C₂H₂O₄: C, 71.21, H, 5.33, N, 9.03; Found:C, 70.87, H, 5.11, N, 9.05.

EXAMPLE 122 N-(4-Benzyloxyphenyl)-N′-benzyl-N′-phenylguanidine.oxalate

White solid: mp: 180° C.; ¹H NMR (300 MHz, CD₃OD): δ 7.30-7.50 (m, 15H,ArH), 7.20-7.25 (d, J=9 Hz, 2H, ArH), 7.05-7.10 (d, J=9 Hz, 2H, ArH),5.13 (s, 2H, Ph—CH₂O—), 5.08 (s, 2H, Ph—CH₂N—); HPLC: 99.4% pure;MS(EI): m/e 407 (M+ for free base); Anal. Calcd. forC₂₇H₂₅N₃O.C₂H₂O₄.0.5H₂O: C, 68.76, H, 5.57, N, 8.30; Found: C, 68.96, H,5.36, N, 8.47.

EXAMPLE 123N-(3-Benzyloxyphenyl)-N′-(4-benzylthiophenyl)guanidine.mesylate((3-(C₆H₄CH₂O)C₆H₄)NHC(═NH)NH(4-(C₆H₄CH₂S)C₆H₄)mesylate)

White solid: mp: 142-143° C.; ¹H NMR (300 MHz, CD₃OD): δ 7.19-7.45 (m,15H, ArH), 6.88-7.00 (m, 18H, ArH), 5.12 (s, 2H, S—CH₂), 4.20 (s, 2H,O—CH₂) 2.70 (s, 3H, Mesylate CH₃); HPLC: 96.6% pure; MS(EI): m/e 440 (M+for free base); Anal. Calcd. for C₂₇H₂₅N₃OS.CH₃SO₃H: C, 62.78, H, 5.46,N, 7.84; Found: C, 62.83, H, 5.49, N, 7.83.

EXAMPLE 124 N,N′-Bis(4-(pentylthio)phenyl)guanidine.HBr

White solid: mp: 153° C.; ¹H NMR (300 MHz, CD₃OD): δ 7.41-7.90 (m, 18H,ArH); MS(EI): m/e 427 (M+ for free base); Anal. Calcd. forC₂₆H₂₁N₃S₂.HBr.0.5H₂O: C, 58.02, H, 4.48, N, 8.12; Found: C, 57.94, H,4.27, N, 8.09.

EXAMPLE 125 N,N′-Bis(3-(phenylthio)phenyl)guanidine.oxalate

White solid: mp: 108° C.; MS(EI): m/e 415 (M+ for free base); Anal.Calcd. for C₂₅H₃₅N₃O₄S₂.0.75H₂O: C, 57.83, H, 7.09, N, 8.09; Found: C,57.94, H, 6.71, N, 8.34.

EXAMPLE 126 N-15-Acenaphthyl)-N′-(2-phenylethyl)guanidine.HCl

Yellow solid: mp: 98-101° C.; R_(f)=0.13 (10:1; CHCl₃/MeOH): ¹H NMR (300MHz, CD₃OD): δ 7.25-7.57 (m, 10H, ArH), 3.56-3.59 (Brs, 2H, CH₂),3.40-3.49 (m, 4H, CH₂), 2.90-2.94 (t, 2H, J=14 Hz, CH₂); MS(EI): m/e 315(M+ for free base); Anal. Calcd. for C₂₁H₂₁N₃.HCl: C, 71.68, H, 6,30, N,11.94; Found: C, 71.44, H, 6.26, N, 11.77.

EXAMPLE 127 N-(5-Acenaphthyl)-N′-(3-butoxypropyl)guanidine.HCl

Brown semicrystalline solid: R_(f)=0.19 (10:1; CHCl₃/MeOH): ¹H NMR (300MHz, CD₃OD): δ 6.62-7.57 (m, 5H, ArH), 3.31-3.49. (m, 10H, CH₂),1.61-1.65 (m, 2H, CH₂), 1.31-1.44 (m, 2H, CH₂), 1.25-1.31 (m, 2H, CH₂)1.20-1.25 (m, 3H, CH₃); MS(EI): m/e 325 (M+ for free base); Anal. Calcd.for C₂₀H₂₇N₃O.HCl: C, 66.37, H, 7.80, N, 11.61; Found: C, 71.80, H,7.27, N, 8.71.

EXAMPLE 128 N,N′-Bis(2,2-diphenylethyl)guanidine.HBr

White solid: mp: 179-180° C., R_(f)=0.20 (10:1; CHCl₃/MeOH): ¹H NMR (300MHz, CD₃OD): δ 7.21-7.36 (m, 20H, ArH), 3.76-3.79 (m, 4H, CH₂); MS(EI):m/e 420 (M+ for free base); Anal. Calcd. for C₂₉H₂₉N₃.HBr: C, 69.6, H,6.04, N, 8.4; Found: C, 69.43, H, 5.96, N, 8.27.

EXAMPLE 129 N-(4-Butoxyphenyl)-N-(4-chlorobenzhydryl)guanidine.HCl

Purple solid: mp: 81-82° C.; R_(f)=0.53 (10:2; CHCl₃/MeOH); ¹H NMR (300MHz, CD₃OD): δ 6.15-7.40 (m, 13H, ArH), 3.94-3.99 (m, 2H, CH₂),1.69-1.81 (m, 2H, CH₂), 1.42-1.55 (m, 2H, CH₂), 0.95-1.0 (m, 3H, CH₃);MS(CI): m/e 408 (M₊ for free base); Anal. Calcd. forC₂₄H₂₆N₃OCl.HCl.1/3H₂O: C, 63.85, H, 6.61, N, 4.73; Found: C, 63.80, H,6.33, N, 9.59.

EXAMPLE 130 (5-Acenaphthyl)-N′-(phenethyl)-N′-benzylguanidine.maleate

White solid: mp: 160° C.; ¹H NMR 1300 MHz, CD₃OD): δ 7.30-7.52 (m, 14H,ArH), 7.13-7.19 (m, 2H, ArH), 6.23 (s, 2H, maleate H), 4.83 (s, 2H,N-benzyl), 3.84-3.91 (t, 2H, N—CH₂), 3.40-347 (Brs, 4H, AcenaphthylCH₂), 3.06-3.12 (t, J=7 Hz, 2H, Ph—CH₂—); MS(EI): m/e 406 (M⁺ for freebase); Anal. Calcd. for C₂₈H₂₇N₃.C₄O₄: C, 73.68, H, 5.99, N, 8.06;Found: C, 73.80, H, 6.09, N, 8.10.

EXAMPLE 131N-4-Benzyloxyphenyl)-N′-(3-benzyloxyphenyl)-N′-(4-chlorobenzyl)guanidine.mesylate

White solid: mp: 145-147°; R_(f)=0.30 (10:1; CHCl₃/MeOH); ¹H NMR (300MHz, CD₃OD): δ 6.91-7.45 (m, 22H, ArH), 5.12 (s, 2H, CH₂), 5.06 (s, 2H,CH₂), 5.01 (s, 2H, CH₂), 2.70 (s, 3H, CH₃); MS(EI): m/e 548 (M⁺ for freebase); Anal. Calcd. for C₃₄H₃₀N₃O₂Cl.CH₃SO₃H: C, 62.67, H, 5.56, N,6.27; Found: C, 62.82, H, 5.42, N, 6.73.

EXAMPLE 132 N,N′-Bis(4-benzyloxyphenyl)-N′-methylguanidine.mesylate

White solid: mp: 168-171° C.; R_(f)=0.14 (10:1; CHCl₃/MeOH); ¹H NMR (300MHz, CD₃OD): δ 7.32-7.45 (m, 12H, ArH), 7.06-7.22 (m, 6H, ArH),5.11-5.14 (d, 4H, J=8 Hz, CH₂), 3.42 (s, 3H, CH₃), 2.69 (s, 3H, CH₃);MS(EI): m/e 437 (M⁺ for free base); Anal. Calcd. forC₂₈H₂₇N₃O₂.CH₃SO₃H.1/4H₂O: C, 64.72, H, 5.90, N, 7.81; Found: C, 64.56,H, 5.87, N, 7.80.

EXAMPLE 133N-(3-Benzyloxyphenyl)-N′-(4-benzyloxyphenyl)-N′-phenylguanidine.HCl

White, grey solid: mp: 72-74° C.; R_(f)=0.20; (10:1; CHCl₃/MeOH); ¹H NMR(300 MHz, CD₃OD): δ 7.21-7.43 (m, 18H, ArH), 7.00-7.03 (d, 2H, J=9 Hz,ArH), 6.70-6.79 (m, 3H, ArH), 5.08 (s, 4H, CH₂); MS(CI): m/e 500 (M⁺ forfree base); Anal. Calcd. for C₃₃H₂₉N₃O₂.HCl: C, 73.94, H, 5.64, N, 7.84;Found: C, 74.09, H, 5.41, N, 7.96.

EXAMPLE 134N-(4-sec-Butylphenyl)-N′-(4-isopropoxyphenyl)-N′-phenylguanidine.HCl

White solid: mp: 190-192° C.; R_(f)=0.59 (10:2; CHCl₃/MeOH); ¹H NMR (300MHz, CD₃OD): δ 6.97-7.51 (m, 13H, ArH), 4.59-4.89 (m, 1H, CH), 2.58-2.68(m, 1H, CH), 1.53-1.66 (m, 2H, CH₂) 1.28-1.32 (m, 6H, CH₃), 1.20-1.25(m, 3H, CH₃), 0.79-0.84 (m, 3H, CH₃); MS(Cl): m/e 402 (M⁺ for freebase); Anal. Calcd. for C₂₆H₃₁N₃O.HCl.1/2H₂O: C, 68.48, H, 7.51, N,9.21; Found: C, 69.81, H, 7.30, N, 9.89.

EXAMPLE 135N-(4-Benzyloxyphenyl)-N′-(4-benzyloxyphenyl)-N′-phenylguanidine.mesylate

White solid: mp: 168-170° C.; R_(f)=0.59 (9:3; EtOAc/MeOH); ¹H NMR (300MHz, CD₃OD): 7.21-7.46 (m, 19H, ArH), 7.04-7.11 (m, 4H, ArH), 5.10-5.11(m, 4H, CH₂), 2.69 (s, 3H, CH₃); MS(El): m/e 499 (M⁺ for free base);Anal. Calcd. for C₃₃H₂₉N₃O₂.1.5CH₃SO₃H: C, 63.97, H, 5.24, N, 6.51;Found: C, 63.97, H, 5.09, N, 6.57.

EXAMPLE 136 N,N′-Bis(3-octyloxyphenyl)guanidine.HCl

Light purple solid: mp: 107-108° C.; R_(f)=0.196 (10:1; CHCl₃/MeOH); ¹HNMR (300 MHz, CD₃D): δ 7.32-7.38 (t, 2H, J=10 Hz, ArH), 6.88-6.91 (m,6H, ArH), 4.01-4.89 (m, 4H, CH₂), 1.75-1.80 (m, 4H, CH₂), 1.40-1.47 (m,4H, CH₂), 1.31-1.40 (m, 16H, CH₂), 0.88-0.93 (t, 6H, J=8 Hz, CH₃);MS(EI): m/e 467 (M⁺ for free base); Anal. Calcd. forC₂₉H₄₅N₃O₂.HBr.1/2H₂O: C, 62.56, H, 8.52, N, 7.55; Found: C, 62.80, H,8.18, N, 7.63.

EXAMPLE 137 N,N′-Bis(4-butoxyphenyl)guanidine.HBr

Cream solid: mp: 88° C.; R_(f)=0.11 (10:1; CHCl₃/MeOH); ¹H NMR (300 MHz,CD₃OD): δ 7.23-7.26 (d, 4H, ArH), 6.99-7.02 (d, 4H, J=9 Hz, ArH),3.98-4.02 (t, 4H, J=13 Hz, CH₂), 1.74-1.79 (m, 4H, CH₂), 1.47-1.54 (m,4H, CH₂), 0.96-1.01 (t, 6H, J=13 Hz, CH₃); MS(El): m/e 355 (M⁺ for freebase); Anal. Calcd. for C₂₁H₂₉N₃O₂.HBr.1.0H₂O: C, 57.80, H, 6.93, N,9.63; Found: C, 55.17, H, 6.77, N, 10.36.

EXAMPLE 138 N,N′-Bis(4-phenoxyphenyl)guanidine.HBr

White solid: mp: 127-128° C.; R_(f)=0.18 (10:1; CHCl₃/MeOH); ¹H NMR (300MHz, CD₃OD): δ 7.31-7.41 (m, 8H, ArH), 7.02-7.18 (m, 10H, ArH); MS(El):m/e 395 (M⁺ for free base); Anal. Calcd. for C₂₅H₂₁N₃O₂.HBr: C, 63.03,H, 4.65, N, 8.82; Found: C, 62.77, H, 4.66, N, 8.84.

EXAMPLE 139 N-(3-Benzyloxyphenyl)-N′-(4-phenoxyphenyl)guanidine.mesylate

White solid: mp: 89-90° C.; R_(f)=0.18 (10:1; CHCl₃:MeOH); ¹H NMR (300MHz, CD₃OD): δ 7.30-7.45 (m, 10H, ArH), 7.15-7.30 (t, 1H, J=10 Hz, ArH),6.91-7.07 (m, 7H, ArH), 5.12 (s, 2H, CH₂), 2.69 (s, 3H, CH₃); MS(EI):m/e 409 (M⁺ for free base); Anal. Calcd. for C₂₆H₃₂N₃O₂.CH₃SO₃H: C,64.14, H, 5.38, N, 8.31; Found: C, 53.85, H, 5.38, N, 8.30.

EXAMPLE 140N-(3-Benzyloxyphenyl)-N′-(4-phenylazophenyl)guanidine.mesylate

Yellow orange solid: mp: 206-208° C.; R_(f)=0.12 (10:1; CHCl₃:MeOH); ¹HNMR (300 MHz, CD₃OD): δ 8.00-8.03 (m, 2H, ArH), 7.91-7.94 (m, 2H, ArH),7.33-7.56 (m, 11H, ArH), 6.94-7.01 (m, 3H, ArH), 5.13 (s, 2H, CH₂), 2.69(s, 3H, CH₃); MS(EI): m/e 421 (M⁺ for free base); Anal. Calcd. forC₂₆H₂₃N₅O.CH₃SO₃H.0.25H₂O: C, 62.11, H, 5.31, N, 13.42; Found: C, 61.86,H, 5.34, N, 13.25.

EXAMPLE 141 N,N′-Bis(3-benzyloxyphenyl)-N′-methylguanidine.HCl

White solid: mp: 41-42° C.; R_(f)=0.44 (10:2; CHCl₃:MeOH); ₁H NMR (300MHz, CD₃OD): δ 7.29-7.45 (m, 12H, ArH), 6.80-7.08 (m, 6H, ArH),5.10-5.12 (d, 4H, J=8 Hz, CH₂), 3.42 (s, 3H, CH₃); MS(EI): m/e 437 (M⁺for free base); Anal. Calcd. for C₂₈H₂₇N₃O₂.HCl.CH₃OH: C, 68.83, H,6.37, N, 8.30; Found: C, 69.13, H, 5.95, N, 8.09.

EXAMPLE 142N-(4-Benzyloxphenyl)-N′-(4-benzyloxyphenyl)-N′-methylguanidine.mesylate

Purple-white solid: mp: 138-140° C.; R_(f)=0.09 (10:1; CHCl₃:MeOH); ¹HNMR (300 MHz, CD₃OD): δ 7.31-7.45 (m, 13H, ArH), 7.11-7.14 (m, 2H, ArH),6.86-7.00 (m, 3H, ArH), 5.10-5.14 (d, 4H, J=10 Hz, CH₂), 3.43 (s, 3H,CH₃), 2.68 (s, 3H, CH₃); MS(EI): m/e 437 (M⁺ for free base); Anal.Calcd. for C₂₈H₂₇N₃O₂.CH₃SO₃H.0.25H₂O: C, 64.72, H, 5.90, N, 7.81;Found: C, 64.73, H, 5.96, N, 7.74.

EXAMPLE 143N-(4-Butoxyphenyl)-N′-(4-isopropoxyphenyl)-N′-phenylguanidine.HCl(4-(CH₃CH₂CH₂CH₂O)C₆H₄)NHC(═NH)N[(4-((CH₃)₂CHO)C₆H₄)][C₆H₅].HCl

Purple solid: mp: 161-164° C.; ¹H NMR (300 MHz, CD₃OD): δ 6.93-7.47 (m,13H, ArH), 4.58-4.62 (m, 1H, CH), 3.94-3.98 (t, 2H, J=13 Hz, CH₂),1.68-1.79 (m, 2H, CH₂), 1.42-1.57 (m, 2H, CH₂), 0.93-1.00 (t, J=15 Hz,3H, CH₃); MS(EI): m/e 418 (M⁺ for free base); Anal. Calcd. forC₂₆H₃₁N₃O₂.HCl: C, 68.78, H, 7.10, N, 9.26; Found: C, 68.79, H, 7.22, N,9.36.

EXAMPLE 144 N-N′-Bis(4-(4-hydroxybutyl)phenyl)guanidine.HBr

Light yellow solid: mp: 143-44° C.; R_(f)=0.16 (10:2; CHCl₃:MeOH); ¹HNMR (300 MHz, CD₃OD): δ 7.23-7.33 (m, 8H, ArH), 3.55-3.59 (m, 4H, CH₂),2.65-2.69 (m, 4H, CH₂), 1.62-1.70 (m, 4H, CH₂), 1.56-1.62 (m, 4H, CH₂);MS(CI): m/e 356 (M⁺ for free base); Anal. Calcd. forC₂₁H₂₉N₃O₂.HBr.0.5H₂O: C, 56.62, H, 7.01, N, 9.43; Found: C, 56.39, H,6.67, N, 9.34.

EXAMPLE 145N-(4-Butoxyphenyl)-N′-(3-methoxyphenyl)-N′-phenylguanidine.HCl

Tan solid: mp: 79-81° C.: R_(f)=0.043 (10:1; CHCl₃:MEOH); ¹H NMR (300MHz, CD₃OD): δ 7.23-7.51 (m, 6H, ArH), 7.23-7.26 (m, 2H, ArH), 6.96-7.02(m, 5H, ArH), 3.95-4.20 (t, 2H, CH₂), 3.80 (s, 3H, CH₂), 1.70-1.80 (m,2H, CH₂), 1.45-1.56 (m, 2H, CH₂), 0.94-1.10 (m, 3H, CH₃); MS(CI): m/e390 (M⁺ for free base); Anal. Calcd. for C₂₄H₂₇N₃O₂.HCl.0.5H₂O: C,66.27, H, 6.72, N, 9.60; Found: C, 65.97, H, 6.69, N, 9.76.

EXAMPLE 146 Inhibition of Glutamate Release

Compounds were tested for the inhibition of glutamate release. As shownby the data below, compounds of the invention are effective blockers ofglutamate release. The assay involves adaptation of a rapid superfusionsystem (said system disclosed in S. Goldin, U.S. Pat. No. 4,891,185(1990); Turner, T. J. et al., Anal. Biochem., 178:8-16 (1989)) tomeasure depolarization-induced ³H-glutamate release from brain nerveterminals. The depolarizing stimulus opens presynaptic voltage-activatedion channels as the key step required to initiate Ca-dependentexocytosis of glutamatergic synaptic vesicles. The method involvespreloading rat brain synaptosomes with ³H-glutamate via the Na-dependentglutamate uptake system. The preloaded nerve terminals are retained in asuperfusion chamber accessed by high-speed, solenoid-driven valves.Microcomputer-operated circuitry controls the timing of valve operation;the valves control the delivery under nitrogen pressure of pulses ofdepolarizing buffer, Ca, and/or drugs to the synaptosomes. The³H-glutamate-containing effluent is continuously collected in a highspeed fraction collector on a subsecond timescale as short as 30 msec(300 msec fractions were employed herein). The high solution flow rateand minimal dead volume of the superfusion chamber, afford rapidsolution changes and precise control of the chemical microenvironment ofthe nerve terminal preparation.

More specifically, the assay method employed was as described in Goldinet al., PCT/US92/01050, with the following modifications. Introductionof a buffer containing high [K⁺] was the means employed to produce thedepolarization. This mode of depolarization is the preferred method ofopening presynaptic voltage-activated Ca channels to trigger glutamaterelease. An additional method of depolarization was also employed,namely introduction of veratridine, and a parallel set of suchveratridine-based experiments was performed. Veratridine is known tostimulate neurotransmitter release by opening voltage-activated Nachannels, which results in depolarization of the nerve terminal plasmamembrane and in turn, secondarily, opens presynaptic Ca channels todirectly trigger ³H-glutamate release via Ca-dependent exocytosis. Theuse of veratridine-induced glutamate release was employed to detectcompounds of the invention which may block neurotransmitter release byblocking voltage-activated presynaptic Na channels. It has beenpreviously reported that tetrodotoxin, a highly specific blocker of TypeI and Type II neuronal Na channels, blocks veratridine-induced³H-glutamate release with no effect on high [K⁺]-induced ³H-glutamaterelease (Katragadda et al. Abs. Soc. for Neurosci. 19:1750 (1993)). Inexperiments measuring veratridine-induced glutamate release, 50 μMveratridine in “basal” buffer was substituted for the “high-K buffer”employed as described in PCT/US92/01050; the protocol was otherwiseidentical to that described therein. In superfusion solutions containingcompounds to be tested, compounds were made as stock solutions inmethanol and diluted so that the final concentration of methanol neverexceeded 0.3% (v/v). All solutions including compound free controlscontained the same solvent [methanol]. Results are shown in the belowtables (1a-1f) identified together as Table I. In that Table and tablesof other examples which follow, the designation “FB” refers to the freebase form of the specified compound.

TABLE 1 Inhibition of ³H-glutamate release in brain nerve terminalpreparations Table 1a: Compounds of Formula IA % Inhibition of Example³H-Glu Rel No. Name @ 3 μM @ 1 μM Salt  1N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)guanidine 61  67* HCl  2N-(5-acenaphthyl)-N-(4-tert-butylbenzyl)guanidine 61  52  FB 19N-(5-acenaphthyl)-N-(4-iso-propylbenzyl)guanidine 81* HCl 23N-(4-sec-butylphenyl)-N-(transcinnamyl)guanidine 33* HCl 24N-(4-n-butoxyphenyl)-N-(4-tert-butylbenzyl)guanidine 62* HCl 27N-(3-trifluoromethoxyphenyl)-N-4-tertbutylbenzyl)guanidine 24  HCl 47N-(1-naphthyl)-N-(4-tert-butylbenzyl)guanidine 40  HCl 48N-(3-iodophenyl)-N-(4-tert-butylbenzyl)guanidine 23* HCl 49N-(4-chloronaphthyl)-N-(4-tert-butylbenzyl)guanidine 32* HCl 52N-(1-naphthylmethyl)-N′-(4-tert-butylbenzyl)guanidine 55* HCl 53N-(5-acenaphthyl)-N-(3-phenoxybenzyl)guanidine 37  HCl 58N-(5-acenaphthyl)-N-(4-iodobenzyl)guanidine 43  HCl.3/2H₂O 59N-(5-acenaphthyl)-N-(4-trifluoromethoxybenzyl)guanidine 44  HCl.2H₂OTable 1b: Compounds of Formula II % Inhibition of Example ³H-Glu Rel No.Name @ 3 μM @ 1 μM Salt  9 N-N′-bis(fluoranthyl)guanidine 17* HBr Table1c: Compounds of Formula IIIA % Inhibition of ³H-Glu Rel Example @ @ @No. Name 3 μM 1 μM 0.3 μM Salt  3N-(5-acenaphthyl)-N′-benzhydrylguanidine 53  HCl 10N-(5-acenaphthyl)-N′-(1-naphthylmethylene)guanidine 71* 24* mesylate 40N-(5-acenaphthyl)-N′-(1-methyl-2-(4-chlorophenyl)ethyl) 64  46 HClguanidine 41 N-(5-acenaphthyl)-N′(1,2-diphenylethyl)guanidine 52  HCl 42N-(5-acenaphthyl)-N′-(3-phenylpropyl)guanidine 60* HCl 43N-(5-acenaphthyl-N′-(2-methyl-2-phenyethyl)guanidine 60  43* HCl 44N-(5-acenaphthyl)-N′-(2-methyl-2-phenylethyl)guanidine 71* 43* HCl 60N-(5-acenaphthyl)-N′-((4-tert-butyl-phenyl)-(4-sec- 32  HClbutylphenyl)-methyl)guanidine Table 1d: Compounds of Formula IV %Inhibition of ³H-Glu Rel Example @ @ @ No. Name 3 μM 1 μM 0.3 μM Salt  4N,N′-bis(4-sec-butylphenyl)guanidine 85 52 FB  5N,N′-bis(4-sec-butylphenyl)-N-methyl guanidine  68* HCl  6N,N′-bis(4-sec-butylphenyl)-N,N′-bismethyl guanidine 92 71 HCl  8N,N′-bis(4-sec-butylphenyl)-2-iminopyrimidazolidine 50 HBr 13N,N′-bis(4-tert-butylphenyl)guanidine 70  62* FB 14N-(4-tert-butylphenyl)-N′-(2,3,4-trichloro phenyl)guanidine 63 HCl 15N-(4-methoxynaphthyl)-N′-(2,3,4-trichlorophenyl)guanidine 88 HCl 30N-N′-bis(3-biphenyl)guanidine 25 31N,N′-di-(3-tert-butylphenyl)guanidine 24 HBr 34N,N′-bis-(3-sec-butylphenyl)guanidine 63 HBr 35N,N′-bis(4-tert-butylphenyl)-N-methylguanidine 61 HCl 36N,N′-bis(4-tert-butylphenyl)-N,N′-methylguanidine 67 FB 37N,N′-bis(4-n-butylphenyl)guanidine 100  57 mesylate 42N-(3-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)guanidine 90 54 HCl 45N,N′-bis(sec-butylphenyl)-N′-(2-phenoxyethyl)guanidine 57 HCl 46N,N′-bis(sec-butylphenyl)-N′-(n-pentyl)guanidine 100  65 HCl Table 1e:Compounds of Formula V % Inhibition of Example ³H-Glu Rel No. Name @ 3μM @ 1 μM Salt  7N-(5-acenaphthyl)-N′-(1,2,3,4-tetrahydroquinolinyl)guanidine 16 20Mesylate 29 N-(5-acenaphthyl)-N-(indolynyl)guanidine 22 FB *Results ofveratridine-induced glutamate release assay as specified above. Table1f: Additional Compounds of the Invention (Including Compounds ofFormulas I-V) % Inhibition of ³H-Glu Rel Ex. No. Name @ 3 μM @ 1 μM @0.3 μM @ 0.1 μM Salt 62 N-(3-sec-butylphenyl)-N-(4-tert- 22 HClbutylbenzyl)guanidine 63 N-(3-tert-butylphenyl)-N-(4-tert- 40 HClbutylbenzyl)guanidine 64 N-(3-pentoxyphenyl)-N-(4-tert-butylbenzyl) 41HCl guanidine 65 N-(5-acenaphthyl)-N-(4-benzyloxybenzyl) 42 HClguanidine 66 N-(4-sec-butylphenyl)-N-(4- 54 HClbenzyloxybenzyl)guanidine 67 N-(4-benzyloxyphenyl)-N-(4- 36 HClbenzyloxybenzyl)guanidine 68 N-(5-acenaphthyl)-N-(3-benzyloxybenzyl) 76HCl guanidine 72 N-(4-sec-butylphenyl)-N-(4-t-butylbenzyl)- 48 HClN′-pyrrolidinylguanidine 73 N-(4-sec-butylphenyl)-N-(4-t-butylbenzyl)-59 HCl N′-(4-thiomorpholinyl)guanidine 74N-(4-sec-butylphenyl)-N-(4-tert- 100  21 HClbutylbenzyl)-N′-piperidinylguanidine 75 N-(4-sec-butylphenyl)-N-(4-tert-42 HCl butylbenzyl)-N′-(4-morpholinyl)guanidine 76N-(4-sec-butylphenyl)-N-(4-tert- 45 HCl butylbenzyl)-N′-(4-propylpiperidinyl)guanidine 77N-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)- 44 HClN′-(4-piperidinyl)guanidine 78 N-(4-sec-butylphenyl)-N-(4-tert- 22mesylate butylbenzyl)-N′-(4-benzylpiperidinyl) guanidine 79N-(4-benzyloxyphenyl)-N-(4-tert- 77 HClbutylbenzyl)-N′-(4-morpholinyl)guanidine 80N-(4-sec-butylphenyl)-N-(4-tert- 68 HCl butylbenzyl)-N′-(1,2,3,4-tetrahydroisoquinolinyl)guanidine 82 N-(4-sec-butylphenyl)-N-(4-tert- 60HCl butylbenzyl)-N′-(3,5-dimethyl-4- morpholinyl)guanidine 83N-(4-sec-butylphenyl)-N-(4-tert- 63 31 HClbutylbenzyl)-N′-(4-sec-butylphenyl)- N′-(methyl)guanidine 84N-(4-sec-butylphenyl)-N-(4-tert- 37 HClbutylbenzyl)-N′-(4-sec-butylphenyl)-N′- (methyl)guanidine 85N-(4-sec-butylphenyl)-N-(4-tert- 100  55 HClbutylbenzyl)-N′-(phenyl)guanidine 86 N-(4-sec-butylphenyl)-N-(4-tert- 4516 HCl butylbenzyl)-N′-(4-chlorophenyl)guanidine 87N-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)- 36 HCl N′-(phenyl)guanidine88 N-(4-sec-butylphenyl)-N-(4-tert- 77 HClbutylbenzyl)-N′-(phenyl)-N′-methylguanidine 89N-(4-sec-butylphenyl)-N-(4-tert- 21 HClbutylbenzyl)-N′-(3,4-dichlorophenyl) guanidine 90N-(4-hexylphenyl)-N-(4-hexylbenzyl)-N′- 42 HCl phenylguanidine 91N-(4-sec-butylphenyl)-N-(4-tert- 49 mesylatebutylbenzyl)-N′-(4-benzyloxyphenyl) guanidine 92N,N′-bis-(4-tert-butylphenyl)-N-N′- 45 HBr dimethylguanidine 93N-(4-benzyloxyphenyl)-N′-(4-tert- 91 48 HCl butylphenyl)guanidine 94N,N′-bis-(3-(1′-methyl-2′-phenyl)ethyl) 66 HCl guanidine 95N-methyl-N-4-benzyloxyphenyl-N′-(4-tert- 100  44 mesylatebutylphenyl)guanidine 96 N,N′-bis-(4-hexylphenyl)guanidine 54 54mesylate 97 N-(3-(1-(4′-ethoxy)benzyl)phenethyl)-N′- 31 mesylate(4-tert-butylphenyl)guanidine 98N-(4-benzyloxyphenyl)-N′-methyl-N-(4-tert- 28 mesylatebutylphenyl)guanidine 99 N-(3-(4-tert-butylbenzyloxy)phenyl)-N′-(4- 20mesylate tert-butylphenyl)guanidine 100 N-(3-(1′-benzylbutyl)phenyl-N′-(4-tert- 20 mesylatebutylphenyl)guanidine 101  N,N′-bis-(4-butylphenyl)-N-methylguanidine 35HCl 102  N-N′-bis-(4-tert-butylphenyl)-N-N′- 73 18 HCl dimethylguanidine103  N-(3-naphthylmethyleneoxyphenyl)-N′-(4- 50 mesylatetert-butylphenyl)guanidine 104  N-(4-benzyloxyphenyl)-N′-(4-butylphenyl)76 HCl guanidine 105  N,N′-bis-(4-butylphenyl)-N-butylguanidine 86 24HCl 106  N-3-(benzyloxymethyl)phenyl-N′-(4-tert- 48 mesylatebutylphenyl)guanidine 107  N-(3,4-bis-butyloxyphenyl)-N′-(4-tert- 34oxalate butylphenyl)guanidine 108 N-(3-benzyloxy)phenyl-N′-(tert-butylphenyl) 49 mesylate guanidine 109 N,N′-bis-(3-butoxy-4-methoxy)phenyl- 86 HCl guanidine 110 N-(4-benzyloxyphenyl), methyl-N′-(4- 77 mesylate butylphenyl)guanidine111  N,N′-bis-(5-tetralinyl)guanidine 61 HBr 117 N-(5-acenaphthyl)-N′-(1-benz[cd]indolinyl) 39 HCl guanidine 138 N-(bis(4-phenoxyphenyl)guanidine 57 HBr —N,N′-bis(benzyloxyphenyl)guanidine 46 mesylate —N-(4-benzyloxyphenyl)-N′-(4- 81 mesylate benzylthiophenyl)guanidine 140 N-(3-benzyloxyphenyl-N′-(4-(azophenyl) 44 mesylate phenyl)guanidine —N,N′-bis(3-benzyloxyphenyl)-N′- 67 HCl methylguanidine —N-(3-benzyloxyphenyl)-N′-(4- 55 mesylatebenzyloxyphenyl)-N′-methylguanidine — N,N′-bis(4-benzyloxyphenyl)-N′- 22mesylate methylguanidine

EXAMPLE 147 Inhibition of ⁴⁵Ca Uptake Through Presynaptic Ca Channels

Compounds of the invention were tested to determine their ability toinhibit voltage-activated calcium channels in nerve terminals ofmammalian brain. Said voltage-activated calcium channels directlycontrol neurotransmitter release (see Nachsen, D. A. et al., J. GenPhysiol., 79:1065-1087 (1982)). The uptake of ⁴⁵Ca into brainsynaptosomes was performed by an adaptation of the method of Nachsen andBlaustein (J. Physiol., 361:251-258 (1985)), as previously described[Goldin et al., PCT/US92/01050]. The principle of the method involvesopening ion permeation through synaptosomal calcium channels by highK⁺-induced depolarization of the synaptosomal preparation. The rapidcomponent of ⁴⁵Ca uptake measured by this procedure is mediated bypresynaptic calcium channels.

Briefly, synaptosomes are prepared by the method of Hajos (Brain Res.,93:485-489 (1975)). Freshly prepared synaptosomes (8 μl) were suspendedIn low potassium “LK” buffer (containing 3 mM KCl). Test compounds in 8μl LK were added to synaptosomes to final concentrations ranging from0.3 μM to 100 μM, and the mixture was preincubated for 5 minutes at roomtemperature. ⁴⁵Ca uptake was then initiated by adding isotope in eitherLK or in buffer (“HK”) containing high [potassium] (150 mM KCl). After 5seconds, the ⁴⁵Ca uptake was stopped by adding 0.9 ml quench buffer(LK+10 mM EGTA). This solution was then filtered under vacuum and thefilters washed with 15 ml of quench buffer.

Washed filters were subjected to scintillation spectrophotometry todetermine the extent of ⁴⁵Ca uptake. Net depolarization-induced ⁴⁵Cauptake was determined for each concentration of each compound tested, asthe difference between ⁴⁵Ca uptake in HK and LK buffers. Results wereplotted as % inhibition of depolarization-induced ⁴⁵Ca uptake vs.[compound] for each compound tested. Representative IC₅₀ for inhibitionof depolarization-induced ⁴⁵Ca uptake are presented below in the tables(2a-2d) below which together are identified as Table 2.

TABLE 2 Inhibition of ⁴⁵Ca uptake through presynaptic Ca channels Table2a: Compounds of Formula IA IC₅₀, block of Example ₄₅Ca uptake, No. NameμM Salt 1 N-(4-sec-butylphenyl)-N-(4- 6.1 HCl tert-butylbenzyl)guanidine2 N-(5-acenaphthyl)-N-(4-tert- 8.1 FB butylbenzyl)guanidine Table 2b:Compounds of Formula IIIA IC₅₀, block of Example ⁴⁵Ca uptake, No. NameμM Salt 9 N-(5-acenaphthyl)-N′-(1- 7.8 Mesylatenaphthyl-methylene)guanidine Table 2c: Compounds of Formula IV IC₅₀,block of Example ⁴⁵Ca uptake, No. Name μM Salt 4N,N′-bis(4-sec-butylphenyl) 11.2 HCl guanidine 6N,N′-bis(4-sec-butylphenyl)- 5.9 HCl N,N′-bismethyl guanidine 13 N,N′-bis(4-tert-butylphenyl) 1.5 FB guanidine 15 N-(4-methoxynaphthyl)-N′- 1.7 HCl (2,3,4-trichlorophenyl)guanidine

EXAMPLE 148 Inhibition of ⁴⁵Ca Uptake Through L-type(Dihydropyridine-sensitive) Calcium Channels

Compounds of the invention representative of each of the major classesof agents claimed herein were tested to determine their ability toinhibit voltage-activated, dihydropyridine-sensitive L-type calciumchannels in clonal GH4C1 pituitary cells. Said voltage-activated L-typecalcium channels are found in cardiac muscle, vascular smooth muscle,and the cardiac Purkije cell conduction system. They are the sites ofaction of the major classes of Ca antagonists employed to treathypertension, angina, cardiac arrhythmias, and related disorders. L-typeCa channels are also the sites of action of certain neuroprotectivedihydropyridine Ca antagonists such as nimodipine.

The uptake of ⁴⁵Ca into GH4C1 cells was performed by an adaptation ofthe method of Tan, K. et al. (J. Biol. Chem., 259:418-426 (1984)). Theprinciple of the method involves activating ion permeation throughsynaptosomal calcium channels by high K⁺-induced depolarization of thesynaptosomal preparation. The uptake of ⁴⁵Ca measured by this procedureis mediated by presynaptic L-type calcium channels, and is sensitive todihydropyridine, phenylalkylamine, and benzothiazipine Ca antagonists attherapeutically relevant concentrations [Tashjian et al., ibid.]. Theadaptation of the aforementioned method involves growing GH4C1 cells in96-well culture plates, and is designed to provide a rapid andquantitative determination of the potency of various compounds ininhibiting ⁴⁵Ca uptake through L-type Ca channels.

Details of Method:

GH4 cells, stored in liquid nitrogen, are suspended in 15 ml growthmedium (Ham's F-10 medium plus 15% heat-inactivated horse serum and 2.5%heat-inactivated fetal bovine serum). The cells are centrifuged,resuspended, and then added to T-75 flasks containing 12-15 mls GrowthMedium, and incubated at 37° C. for approximately 1 week. The cells arethem removed from the T75 flask after dissociation from the walls of theflask by treatment for 5 minutes at 37° C. with 1 mg/ml Viocase. TheViocase is decanted, and the cells are resuspended in ˜200 ml of GrowthMedium. The cells are then aliquoted (200 μl/well) into each well ofseveral 96 well plates. The cells are then grown under theaforementioned conditions for 3-4 weeks, with replacement of GrowthMedium occurring twice per week. Cells are fed growth medium 24 hoursbefore they are employed for ⁴⁵Ca uptake determinations.

At the time of the assay, media Is aspirated from each 96-well plateusing a manifold designed to allow 50 μL of liquid to remain in eachwell. Each plate is washed and aspirated twice with a low K⁺ buffersolution “LKHBBS” (in mM 5 KCl, 145 NaCl, 10 Hepes, 1 MgCl₂, 0.5 MgCl₂,10 glucose, pH 7.4), 200 μl/well. Each plate is incubated for 10 minutesat 37° C., and aspirated as above. To each well of each plate, 50 μl ofHBBS containing the drug to be tested in twice the final concentrationis added. The plates are incubated for 10 minutes at room temperature.To each well of each plate, 50 μl of either of two solutions are added:

(a) LKHBBS containing 1 μCi of carrier-free ⁴⁵Ca, or

(b) HKHBBS (a high K⁺ buffer containing 150 mM KCl and no NaCl, butotherwise identical to LKHBBS).

Each plate is then incubated for 5 minutes at room temperature,aspirated as above, and quenched with 200 μl/well of Quench Buffer(Ca-free LKHBBS containing 10 mM Tris-EGTA). Each plate is aspirated andrinsed with Quench Buffer a second time, then carefully aspirated todryness. To each well of each plate 100 μl of High Safe II scintillationfluid is added. The plates are sealed, shaken, and subjected toscintillation spectrophotometry on a Microbeta 96-well ScintillationCounter (Wallac, Gaithersburg, Md., USA).

Net depolarization-induced ⁴⁵Ca uptake was determined for eachconcentration of each compound tested, as the difference between ⁴⁵Cauptake in HKBBS and LK buffers. Results were plotted as % inhibition ofdepolarization-induced ⁴⁵Ca uptake vs. [compound] for each compoundtested. Representative IC₅₀ for inhibition of depolarization-induced⁴⁵Ca uptake are presented below in the tables (3a-3c) below whichtogether are identified as Table 3. The known compounds of verapamil anddiltiazem were also tested pursuant to the same protocol as specifiedabove and the following activity against L-type Ca channels wasobserved: verapamil: IC₅₀ (block of ⁴⁵Ca uptake, μM) 8.0+/−4 (n=3);diltiazem: IC₅₀ (block of ⁴⁵Ca uptake, μM) 19.7+/−6 (n=3).

TABLE 3 Inhibition of ⁴⁵Ca uptake through L-type Ca channels Table 3a:Compounds of Formula IA IC₅₀, block of Example ⁴⁵Ca uptake, No. Name μMSalt 1 N-(4-sec-butylphenyl)-N-(4-tert- 1.7 FB butylbenzyl)guanidine 2N-(5-acenaphthyl)-N-(4-tert- 2.1 FB butylbenzyl)guanidine 19 N-(5-acenaphthyl)-N-(4-iso- 2.1 HCl propylbenzyl)guanidine Table 3b:Compounds of Formula IIIA IC₅₀, block of Example ⁴⁵Ca uptake, No. NameμM Salt 3 N-(5-acenaphthyl)-N′-(benz- 2.7 HCl hydryl)guanidine Table 3c:Compounds of Formula IV IC₅₀, block of Example ⁴⁵Ca uptake, No. Name μMSalt 4 N,N′-bis(4-sec-butylphenyl) 2.1 FB guanidine 6N,N′-bis(4-sec-butylphenyl)-N, 4.3 HCl N′-bismethyl guanidine 13 N,N′-bis(4-tert-butylphenyl) 4.1 FB guanidine 15 N-(4-methoxylnaphthyl)-N′- 1.7 HCl (2,3,5-trichiorophenyl)guanidine

EXAMPLE 149 Inhibition of ⁴⁵C-guanidine Uptake Through Type II NeuronalVoltage-activated Sodium Channels

Antagonists of the neuron-specific type II subclass of voltage-gated Nachannels are neuroprotective (Stys, P. K. et al., J. Neurosci.,12:430-439 (1992)). The ability of compounds of the invention to blockvoltage-activated Type II Na channels was determined in a functionalassay employing a Chinese Hamster Ovary (“CHO”) cell line expressingcloned Type II Na channels derived from rat brain (West, J. W. et al.,Neuron 8:59-70 (1992)). The assay is based on the observation thatveratridine, an alkaloid neurotoxin, causes persistent activation ofsodium channels, and tetrodotoxin, a heterocyclic agent derived frompuffer fish, is a potent and highly specific blocker of several majorsubclasses of voltage-sensitive sodium channels, including the said TypeII subclass. It further takes advantage of the finding that guanidiniumcation will permeate through tetrodotoxin-sensitive Na channels whensaid channels are opened, either by membrane depolarization (Hille, B.,Ionic Channels of Excitable Membranes 2nd Edition, Sinauer Associates,Sunderland, Mass., pp. 349-353 (1992)) or by exposure to veratridine(Reith, M. E. A., Eur. J. Pharmacol., 188:33-41(1990)). Accordingly, theassay entails measuring veratridine-stimulated, tetrodotoxin-sensitiveinflux of [¹⁴C]-guanidinium ion through cloned Type II Na channelsexpressed in CHO cells. The protocol of the assay is as follows.

Assay Protocol:

The aforementioned CHO cell line is grown by standard cell culturetechniques in RPMI 1640 medium (Media Tech), supplemented with 5% fetalcalf serum (Hyclone), 200 μg/ml G418 (Sigma) and 5.75 mg/ml proline(Sigma). Cells are routinely allowed to grow for 3-4 days in vitro.

Cultures are rinsed 3 times with 200 μl of “preincubation buffer” (5.4mM KCl, 0.8 mM MgSO₄, 50 mM Hepes, 130 mM choline chloride, 0.1 mg/mlBSA, 1 mM guanidine HCl, 5.5 mM D-glucose, pH 7.4) and incubated with200 μl preincubation buffer at 37° C. for 10 minutes. A 96-channelmanifold connecter is used to vacuum-aspirate the buffer from the wellsbetween rinses.

Different concentrations of the tested compounds are prepared bydilution into “uptake buffer” (preincubation buffer plus ˜2.5 mCi/ml[¹⁴C]-guanidinium HCl, ˜40 mCi/mmol) containing veratridine (100 μM).Aliquots (50 μl) of these working stocks is added to the 96-well platesand incubated at room temperature for 1 hour. The veratridine-induced[¹⁴C]-guanidinium uptake was linear with time and a good signal (4-8fold basal uptake) was obtained following a 1 hour incubation. Thefollowing controls are also conducted in each 96-well plate: basaluptake (obtained in the absence of CNS compound and veratridine), uptakeevoked by veratridine alone, and veratridine evoked uptake in thepresence of 10 μM tetrodotoxin (the latter is a measure of non-specificuptake independent of Na channel activation).

The flux assay is terminated at the end of the incubation period byrinsing the 96-well plates 3 times with 200 μl/well of ice cold “washbuffer” (163 mM choline chloride, 0.8 mM Mg SO₄, 1.8 mM Ca Cl₂, 5 mMHepes, 1 mg/ml BSA). The remaining 50 μl of wash buffer in the wells(following rinsing) is removed by vacuum aspiration with an 8-channelDrummond aspirator. 100 μl of High Safe II scintillation fluid is addedto each well. The plates are sealed before shaking for 15 minutes Theplates are then allowed to sit for 45 minutes before counting in a96-well scintillation counter.

Net veratridine-induced [¹⁴C]-guanidinium uptake was determined for eachconcentration of each compound tested, as the difference between[¹⁴C]-guanidinium uptake in the presence and absence of tetrodotoxin.Results were plotted as % inhibition of veratridine-induced[¹⁴C]-guanidinium uptake vs. [compound] for each compound tested.

Representative IC₅₀'s for inhibition of veratridine-induced[¹⁴C]-guanidinium uptake are presented below in the following tables(4a-4d) which together are identified as Table 4.

TABLE 4 Inhibition of [¹⁴C]-guanidinium uptake through type II sodiumchannels Table 4a: Compounds of Formula IA IC₅₀, block of ¹⁴Cguanidinium Example uptake, No. Name μM Salt  1N-(4-sec-butylphenyl)-N-(4-tert- 0.8 HCl butylphenyl)guanidine  2N-(5-acenaphthyl)-N-(4-tert- 1 FB butylphenyl)guanidine 16N-(4-sec-buty(phenyl)-N- 0.5 FB (benzyl)guanidine 18N-(5-acenaphthyl)-N-(4-iso- 2.1 HCl propylbenzyl)guanidine 20N-(4-cyclohexyl)-N-(4-tert- 0.9 HCl butylbenzyl)guanidine 21N-(fluorenyl)-N-(4-tert- 1.9 HCl butylbenzyl)guanidine 22N-(4-sec-butylphenyl)-N- 0.5 HCl (transcinnamyl)guanidine 24N-(3-biphenyl)-N-(4-tert- 1.8 HCl butylbenzyl)guanidine 26N-(3-trifluoromethoxyphenyl)- 0.7 HCl N-(4-tert-butylbenzyl)guanidine 27N-(4-methoxynaphthyl)-N′-(4- 1.2 HCl tert-butylbenzyl)guanidine 48N-(3-i dophenyl)-N-(4-tert- 0.4 HCl butylbenzyl)guanidin 49N-(4-chloronaphthyl)-N-(4-tert- 2.2 HCl butylbenzyl)guanidine Table 4b:Compounds of Formula II IC₅₀, block of ¹⁴C guanidinium Example ⁴⁵Cauptake, No. Name μM Salt 11 N,N′-bis(fluorenyl)guanidine 0.9 HBr Table4c: Compounds of Formula IIIA IC₅₀, block of Example ⁴⁵Ca uptake, No.Name μM Salt  9 N-(5-acenaphthyl)-N′-(1- 0.7 HClnaphthyl-methylene)guanidine 42 N-(5-acenaphthyl)-N′-(2- 0.7 HClmethyl-3-phenylpropyl) guanidine Table 4d: Compounds of Formula IV IC₅₀,block of ¹⁴C guanidinium Example ⁴⁵Ca uptake, No. Name μM Salt 4N,N′-bis(4-sec-butylphenyl) 0.8 HCl guanidine 6N,N′-bis(4-sec-butylphenyl)-N, 0.6 HCl N′-bismethyl guanidine 8N,N′-bis(4-sec-butylphenyl-2- 0.2 HBr iminopyrimidazolidine 12 N,N′-bis(4-tert-butylphenyl) 1.5 FB guanidine 13 N-(4-tert-butylphenyl)-N′-(2,3, 0.9 HCl 4-trichlorophenyl)guanidine 14 N-(methoxynaphthyl)-N′-(2,3,4- 1.8 HCl trichlorophenyl)guanidine

EXAMPLE 150 In vivo Anticonvulsant Activity in the DBA/2 Mouse Model

The in vivo potency of compounds of the present invention is exemplifiedby data summarized in the Table V below and obtained pursuant to thefollowing protocol.

Compounds were tested for their effectiveness in preventing seizures inDBA/2 mice which have a unique sensitivity to auditory stimulation.Exposure to loud high-frequency sounds can trigger seizure activity inthese animals. This sensitivity develops from postnatal day 12 and peaksaround day 21 and slowly diminishes as the animals mature. The unusualresponse to auditory stimulation in this strain of mouse is believed tobe due to a combination of early myelination (causing an unusually lowexcitatory threshold) and delayed development of inhibitory mechanisms.Glutamate, the predominant excitatory neurotransmitter, has beenimplicated in this response. Blockade of glutamate receptors of the NMDAand AMPA subtypes, prevents audiogenic seizures in these mice. Compoundsthat block the release of glutamate should similarly act to preventseizure activity, and may be therapeutic in other neurologic disorderssuch as stroke, which also involves glutamate-mediated damage.

Mice were injected intraperitoneally with the compound specified inTable V below or with vehicle control, 30 minutes prior to being placedin a bell jar and turning on the auditory stimulus (12 KHz sine wave at110-120 db). Administered doses are specified in Table V as milligram ofcompound per kilogram bodyweight of mouse. The auditory stimulus wasleft on for 60 seconds and mice reactions were timed and recorded.

Percentage inhibition was determined with reference to vehicle controls.Results are shown in the Table 5 below.

TABLE 5 Audiogenic Response Example Dose % No. Compound Name (mg/kg)Inhib. Salt  8 N,N′-bis-(4-sec-butyl-2- 2 41 HBr iminopyrimidazolidine 475 29 N-(5-acenaphthyl)-N′-(indo- 20 42 mesylate linyl)guanidine 40 81 1 N-(4-sec-butylphenyl)-N-(4- 40 91 HCl tert-butylbenzyl)guanidine- 1054 20 80.5 37 N-N′-bis(4-n-butylphenyl) 25 82 mesylate guanidine 40 9272 N-(4-sec-butylphenyl)-N-(4-t- 40 81 HCl butylbenzyl)-N′-pyrrolidinyl-20 52 guanidine — N,N′-bis(4-n-butoxyphenyl) 20 60 guanidine 40 82 73N-(4-sec-butylphenyl)-N-(4-t- 20 23 HCl butylbenzyl)-N′-(4- 40 89thiomorpholinyl)guanidine — N-(4-benzyloxyphenyl)-N′-(4- 20 16phenoxyphenyl)guanidine 40 93 104  N-(4-benzyloxyphenyl)-N′-(4- 20 40HCl butylphenylguanidine 40 90 106  N-3-benzyloxymethyl)phenyl- 40 93mesylate N′-(4-tert-butylphenyl) guanidine 108 N-(3-benzyloxy)phenyl-N′-(4- 40 80 mesylate tert-butylphenyl)guanidine79 N-(4-benzyloxyphenyl)-N-(4- 20 41 HCl tert-butylbenzyl)-N′-(4- 40 68morpholinyl)guanidine 110  N-(4-benzyloxyphenyl)-N- 20 42.3 mesylatemethyl-N′-(4-butylphenyl) 40 92.5 guanidine

The invention has been described in detail with reference to preferredembodiments thereof. However, it will be appreciated that those skilledin the art, upon consideration of this disclosure, may makemodifications and improvements within the spirit and scope of theinvention.

What is claimed is:
 1. A compound having the following formula:

wherein R and R¹ are each independently substituted or unsubstitutedcarbocyclic aryl having at least about 5 ring atoms, substituted orunsubstituted aralkyl having at least about 5 ring atoms, or asubstituted or unsubstituted heteroaromatic or heteroalicyclic grouphaving from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to3 hetero atoms; and pharmaceutically acceptable salts thereof.
 2. Acompound of claim 1 wherein at least one of R and R¹ is substituted orunsubstituted carbocyclic aryl or substituted or unsubstituted aralkyl.3. A compound of claim 1 wherein both R and R¹ are substituted orunsubstituted carbocyclic aryl or substituted or unsubstituted aralkyl.4. A compound of claim 1 wherein both R and R¹ are substituted orunsubstituted carbocyclic aryl.
 5. A compound of claim 1 wherein R andR¹ are substituted or unsubstituted phenyl, substituted or unsubstitutednaphthyl or substituted or unsubstituted benzyl.
 6. A compound of claim1 selected from the group consisting of:N-(4-sec-butylphenyl)-N-benzylguanidine;N-(5-acenaphthyl)-N-benzylguanidine;N-(3-acenaphthyl)-N-benzylguanidine;N-(5-acenaphthyl)-N-(4-isopropylbenzyl)guanidine;N-(3-acenaphthyl)-N-(4-isopropylbenzyl)guanidine;N-(4-cyclohexylphenyl)-N-(4-isopropylbenzyl)guanidine;N-(4-cyclohexylphenyl)-N-(4-tert-butylbenzyl)guanidine;N-(2-fluorenyl)-N-(4-tert-butylbenzyl)guanidine;N-(4-sec-butylphenyl)-N-(cinnamylmethylene)guanidine;N-(4-n-butoxyphenyl)-N-(4-tert-butylbenzyl)guanidine;N-(3-biphenyl)-N-(4-tert-butylbenzyl)guanidine;N-(5-indanyl)-N-(4-tert-butylbenzyl)guanidine;N-(3-trifluoromethoxyphenyl)-N-(4-tert-butylbenzyl)guanidine;N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)guanidine;N-(5-acenaphthyl)-N-(4-tert-butylbenzyl)guanidine;N-(3-acenaphthyl)-N-(4-tert-butylbenzyl)guanidine;N-(methoxy-1-naphthyl)-N-(4-tert-butylbenzyl)guanidine;N-(1-naphthyl)-N-(4-tert-butylbenzyl)guanidine;N-(3-iodophenyl)-N-(4-tert-butylbenzyl)guanidine;N-(4-chloro-1-naphthyl)-N-(4-tert-benzyl)guanidine;N-(4-tert-butylphenyl)-N-(4-tert-butylbenzyl)guanidine;N-(4-iodophenyl)-N-(4-tert-butylbenzyl)guanidine;N-(1-naphthylmethyl)-N-(4-tert-butylbenzyl)guanidine;N-(5-acenaphthyl)-N-(3-phenoxybenzyl)guanidine;N-(3-trifluoromethylphenyl)-N-(4-tert-butylbenzyl)guanidine;N-(3-methylthiophenyl)-N-(4-tert-butylbenzyl)guanidine;N-(5-acenaphthyl)-N-(3-iodobenzyl)guanidine;N-(5-acenaphthyl)-N-(cinnamyl)guanidine;N-(5-acenaphthyl)-N-(4-iodobenzyl)guanidine;N-(5-acenaphthyl)-N-(4-trifluoromethoxybenzyl)guanidine; andpharmaceutically acceptable salts thereof.
 7. A pharmaceuticalcomposition comprising a compound of any one of claims 1 through 6 and apharmaceutically acceptable carrier.